Novel compounds

ABSTRACT

The invention provides compounds of formula (I): 
     
       
         
         
             
             
         
       
     
     Said compounds being modulators of Kv3 channels and of use in the prophylaxis or treatment of related disorders.

TECHNICAL FIELD

This invention relates to novel compounds, pharmaceutical compositionscontaining them and their use in therapy, in particular in theprophylaxis or treatment of hearing disorders, including hearing lossand tinnitus, as well as schizophrenia, bipolar disorder, epilepsy andsleep disorders.

BACKGROUND TO THE INVENTION

The Kv3 voltage-gated potassium channel family includes four members,Kv3.1, Kv3.2, Kv3.3, and Kv3.4. Genes for each of these subtypes cangenerate multiple isoforms by alternative splicing, producing versionswith different C-terminal domains. Thirteen isoforms have beenidentified in mammals to date, but the currents expressed by thesevariants appear similar (Rudy and McBain, 2001, Trends in Neurosciences24, 517-526). Kv3 channels are activated by depolarisation of the plasmamembrane to voltages more positive than −20 mV; furthermore, thechannels deactivate rapidly upon repolarisation of the membrane. Thesebiophysical properties ensure that the channels open towards the peak ofthe depolarising phase of the neuronal action potential to initiaterepolarisation. Rapid termination of the action potential mediated byKv3 channels allows the neuron to recover more quickly to reachsub-threshold membrane potentials from which further action potentialscan be triggered. As a result, the presence of Kv3 channels in certainneurons contributes to their ability to fire at high frequencies (Rudyand McBain, 2001, Trends in Neurosci. 24, 517-526). Kv3.1-3 subtypes arepredominant in the CNS, whereas Kv3.4 channels are found predominantlyin skeletal muscle and sympathetic neurons (Weiser et al., 1994, J.Neurosci. 14, 949-972). Kv3.1-3 channel subtypes are differentiallyexpressed by sub-classes of interneurons in cortical and hippocampalbrain areas (e.g. Chow et al., 1999, J. Neurosci. 19, 9332-9345; Martinaet al., 1998, J. Neurosci. 18, 8111-8125; McDonald and Mascagni, 2006,Neurosci. 138, 537-547, Chang et al., 2007, J. Comp. Neurol. 502,953-972), in the thalamus (e.g. Kasten et al., 2007, J. Physiol. 584,565-582), cerebellum (e.g. Sacco et al., 2006, Mol. Cell. Neurosci. 33,170-179), and auditory brain stem nuclei (Li et al., 2001, J. Comp.Neurol. 437, 196-218).

Characterisation of mice in which one or more of the Kv3 subtypes hasbeen deleted shows that the absence of Kv3.1 gives rise to increasedlocomotor activity, altered electroencephalographic activity, and afragmented sleep pattern (Joho et al., 1999, J. Neurophysiol. 82,1855-1864). The deletion of Kv3.2 leads to a reduction in seizurethreshold and altered cortical electroencephalographic activity (Lau etal., 2000, J. Neurosci. 20, 9071-9085). Deletion of Kv3.3 is associatedwith mild ataxia and motor deficits (McMahon et al., 2004, Eur. J.Neurosci. 19, 3317-3327). Furthermore, reduction of function mutationsof Kv3.3 channels in humans have been associated with spinocerebellarataxia type 13 (Waters et al., 2006, Nat. Genet. 38, 447-451). Doubledeletion of Kv3.1 and Kv3.3 gives rise to a severe phenotypecharacterised by spontaneous seizures, ataxia, and an increasedsensitivity to the effects of ethanol (Espinosa et al., 2001, J.Neurosci. 21, 6657-6665; Espinosa et al., 2008, J. Neurosci. 28,5570-5581).

The known pharmacology of Kv3 channels is limited. Tetraethylammoniumhas been shown to inhibit the channels at low millimolar concentrations(Rudy and McBain, 2001, Trends in Neurosci. 24, 517-526), andblood-depressing substance (BDS) toxins from the sea anemone, Anemoniasulcata (Diochot et al., 1998, J. Biol. Chem. 273, 6744-6749), have beenshown to selectively inhibit Kv3 channels with high affinity (Yeung etal., 2005, J. Neurosci. 25, 8735-8745). In addition to compounds actingdirectly on Kv3 channels, agonists of receptors that activate proteinkinase A (PKA) and protein kinase C (PKC) have been shown to modulateKv3-mediated currents in specific brain areas, leading to a reduction inthe ability of the neurons to fire at high frequency (Atzori et al.,2000, Nat. Neurosci. 3, 791-798; Song et al., 2005, Nat Neurosci. 8,1335-1342); these studies suggest that PKA and PKC can specificallyphosphorylate Kv3 channels in a neuron-specific manner, causing areduction in Kv3-mediated currents.

Bipolar disorder, schizophrenia, anxiety, and epilepsy are seriousdisorders of the central nervous system that have been associated withreduced function of inhibitory interneurons and gamma-amino butyric acid(GABA) transmission (Reynolds et al., 2004, Neurotox. Res. 6, 57-61;Benes et al., 2008, PNAS, 105, 20935-20940; Brambilla et al., 2003, Mol.Psychiatry. 8, 721-37, 715; Aroniadou-Anderjaska et al., 2007, AminoAcids 32, 305-315; Ben-Ari, 2006, Crit. Rev. Neurobiol. 18, 135-144).Parvalbumin positive basket cells that express Kv3 channels in thecortex and hippocampus play a key role in generating feedback inhibitionwithin local circuits (Markram et al., 2004, Nat. Rev. Neurosci. 5,793-807). Given the relative dominance of excitatory synaptic input overinhibitory input to glutamatergic pyramidal neurons in these circuits,fast-firing of interneurons supplying inhibitory input is essential toensure balanced inhibition. Furthermore, accurate timing of inhibitoryinput is necessary to sustain network synchronisation, for example, inthe generation of gamma frequency field potential oscillations that havebeen associated with cognitive function (Fisahn et al., 2005, J. Physiol562, 65-72; Engel et al., 2001, Nat. Rev. Neurosci. 2, 704-716).Notably, a reduction in gamma oscillations has been observed in patientswith schizophrenia (Spencer et al., 2004, PNAS 101, 17288-17293).Consequently, positive modulators of Kv3 channels might be expected toenhance the firing capabilities of specific groups of fast-firingneurons in the brain. These effects may be beneficial in disordersassociated with abnormal activity of these neuronal groups.

In addition, Kv3.2 channels have been shown to be expressed by neuronsof the superchiasmatic nucleus (SCN) the main circadian pacemaker in theCNS (Schulz and Steimer, 2009, CNS Drugs 23 Suppl 2, 3-13).

Hearing loss represents an epidemic that affects approximately 16% ofthe population in Europe and the US (Goldman and Holme, 2010, DrugDiscovery Today 15, 253-255), with a prevalence estimated at 250 millionpeople worldwide (B. Shield, 2006, Evaluation of the social and economiccosts of hearing impairment. A report for Hear-It AISBL:www.hear-it.org/multimedia/Hear_It_Report_October_2006. pdf). As lifeexpectancy continues to increase, so too will the number of peoplesuffering from hearing disorders. Furthermore, it is believed thatmodern lifestyles may exacerbate this burden as the younger generationages. Hearing conditions, including tinnitus have a profound effect onthe quality of life, causing social isolation, depression, work andrelationship difficulties, low self-esteem, and prejudice. Voltage-gatedion channels of the Kv3 family are expressed at high levels in auditorybrainstem nuclei (Li et al., 2001, J. Comp. Neurol. 437, 196-218) wherethey permit the fast firing of neurons that transmit auditoryinformation from the cochlear to higher brain regions. Loss of Kv3.1channel expression in central auditory neurons is observed in hearingimpaired mice (von Hehn et al., 2004, J. Neurosci. 24, 1936-1940),furthermore, a decline in Kv3.1 expression may be associated with lossof hearing in aged mice (Jung et al. 2005 Neurol. Res. 27, 436-440), andloss of Kv3 channel function may also follow noise-trauma inducedhearing loss (Pilati et al., Hear Res. 2012 January 283(1-2):98-106).Furthermore, pathological plasticity of auditory brainstem networks islikely to contribute to symptoms that are experienced by many peoplesuffering from hearing loss of different types. Recent studies haveshown that regulation of Kv3.1 channel function and expression has amajor role in controlling auditory neuron excitability (Kaczmarek etal., 2005, Hearing Res. 206, 133-145), suggesting that this mechanismcould account for some of the plastic changes that give rise totinnitus. These data support the hypothesis that positive modulation ofKv3 channels in auditory brainstem nuclei could have a therapeuticbenefit in patients suffering from hearing loss. Finally, Fragile Xsyndrome and autism are frequently associated with hypersensitivity tosensory input, including auditory stimuli. Recent findings suggest thatthe protein coded by the FMR-I gene, whose mutation or absence givesrise to Fragile X syndrome, may directly regulate the expression ofKv3.1 channels in the auditory brainstem nuclei (Strumbos et al., 2010,J. Neuroscience, in press), suggesting that mis-regulation of Kv3.1channels could give rise to hyperacusis in patients suffering fromFragile X or autism. Consequently, we propose that small moleculemodulators of Kv3 channels in auditory brainstem nuclei could have abenefit in the treatment of disorders of hearing, including tinnitus andauditory hyper-acuity associated with Fragile X syndrome and autism.

Spinocerebellar ataxia type 13 (SCA13) is a human autosomal dominantdisease caused by mutations in the KCNC3 gene that encodes the Kv3.3channel. These mutations have been shown to cause a reduction infunction of the channels (Waters et al., 2006, Nat. Genet. 38, 447-451;Minassian et al., 2012, J Physiol. 590.7, 1599-1614). Coexpression ofKv3.1 and Kv3.3 in many brain areas, including the cerebellum suggestssome redundancy or the ability of one subtype to compensate for theabsence of the other, indeed the phenotype of the Kv3.1/Kv3.3 doubleknockout mice is markedly more severe than either of the two singleknockouts (e.g. Espinosa et al., 2008, J. Neurosci. 28, 5570-5581).Furthermore, it is possible that Kv3.1 and Kv3.3 proteins assemble toform heteromeric channels in some neurons. The ability of Kv3.1 tocompensate for a loss of function of Kv3.3 may explain why certainmutations in the latter are only associated with an onset ofspinocerebellar ataxia later in adult life, rather than from birth(Minassian et al., 2012, J Physiol. 590.7, 1599-1614). Consequently,small molecule modulators of either Kv3.3 or Kv3.1 might be beneficialin the treatment of spinocerebellar ataxia, in particular SCA13.

Patent applications WO2011/069951 and WO2012/076877 disclose compoundswhich are modulators of Kv3.1 and Kv3.2. Further, the value of suchcompounds is demonstrated in animal models of seizure, hyperactivity,sleep disorders, psychosis, cognitive deficit, bipolar disorder andhearing disorders.

There remains a need for the identification of alternative modulators ofKv3.1 and Kv3.2, in particular modulators of Kv3.1 and Kv3.2 which maydemonstrate increased in vivo potency, certain channel selectivityprofiles or desirable pharmacokinetic parameters that reduce the doserequired for therapeutic effect in vivo. For certain therapeuticindications, there is also a need to identify compounds with a differentmodulatory effect on Kv3 channels, for example, compounds that alter thekinetics of channel gating or channel inactivation, and which may behavein vivo as negative modulators of the channels.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula (I):

wherein:W is CR_(a)R_(b) or O;

-   -   when W is CR_(a)R_(b) then Z is CH₂;    -   when W is O then Z is CF₂;        R_(a) and R_(b) are CH₃ or taken together form a C₃ spiro        cycloalkyl;    -   wherein, when W is CR_(a)R_(b), Z is CH₂ and R_(a) and R_(b) are        CH₃:        -   Ring A is:

-   -   -    and Ring B is:

-   -   or        -   Ring A is:

-   -   -    and Ring B is:

-   -   wherein, when W is CR_(a)R_(b), Z is CH₂ and R_(a) and R_(b)        taken together form a C₃ spiro cycloalkyl:        -   Ring A is:

-   -   -    and        -   Ring B is:

-   -   -    and

    -   wherein, when W is O and Z is CF₂:        -   Ring A is:

-   -   -    and Ring B is:

A compound of formula (I) may be provided in the form of apharmaceutically acceptable salt and/or solvate thereof. In oneembodiment of the invention a compound of formula (I) is provided in theform of a pharmaceutically acceptable salt.

The compounds of formula (I) may be used as medicaments, in particularfor the prophylaxis or treatment of hearing disorders, including hearingloss and tinnitus, as well as schizophrenia, bipolar disorder, epilepsyand sleep disorders. The compounds of formula (I) may also be used asmedicaments for the prophylaxis or treatment of cognition impairment orataxia.

Further, there is provided a method for the prophylaxis or treatment ofhearing disorders, including hearing loss and tinnitus, as well asschizophrenia, bipolar disorder, epilepsy and sleep disorders byadministering to a subject a compound of formula (I). There is alsoprovided a method for the prophylaxis or treatment of cognitionimpairment or ataxia by administering to a subject a compound of formula(I).

Compounds of formula (I) may be used in the manufacture of a medicamentfor the prophylaxis or treatment of hearing disorders, including hearingloss and tinnitus, as well as schizophrenia, bipolar disorder, epilepsyand sleep disorders. Compounds of formula (I) may also be used in themanufacture of a medicament for the prophylaxis or treatment ofcognition impairment or ataxia.

Also provided are pharmaceutical compositions containing a compound offormula (I) and a pharmaceutically acceptable carrier or excipient.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds of formula (I):

wherein:W is CR_(a)R_(b) or O;

-   -   when W is CR_(a)R_(b) then Z is CH₂;    -   when W is O then Z is CF₂;        R_(a) and R_(b) are CH₃ or taken together form a C₃ spiro        cycloalkyl;    -   wherein, when W is CR_(a)R_(b), Z is CH₂ and R_(a) and R_(b) are        CH₃:        -   Ring A is:

-   -   -    and Ring B is:

-   -   or        -   Ring A is:

-   -   -    and Ring B is:

-   -   wherein, when W is CR_(a)R_(b), Z is CH₂ and R_(a) and R_(b)        taken together form a C₃ spiro cycloalkyl:        -   Ring A is:

-   -   -    and        -   Ring B is:

-   -   -    and

    -   wherein, when W is O and Z is CF₂:        -   Ring A is:

-   -   -    and Ring B is:

or a pharmaceutically acceptable salt and/or solvate thereof.

Compounds of formula (I) may optionally be provided in the form of apharmaceutically acceptable salt and/or solvate. In one embodiment ofthe invention a compound of formula (I) is provided in the form of apharmaceutically acceptable salt. In a second embodiment of theinvention a compound of formula (I) is provided in the form of apharmaceutically acceptable solvate. In a third embodiment of theinvention a compound of formula (I) is not in the form of a salt orsolvate.

In another embodiment of the invention the compound is selected from thegroup consisting of:

-   (5R)-5-ethyl-5-methyl-3-[2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2,4-dione;-   (5R)-5-ethyl-5-methyl-3-{2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}-2,4-imidazolidinedione;-   (5R)-3-{2-[(2,2-difluoro-7-methyl-1,3-benzodioxol-4-yl)oxy]-5-pyrimidinyl}-5-ethyl-5-methyl-2,4-imidazolidinedione;-   5,5-dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2,4-dione;-   (5R)-5-ethyl-3-[2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2,4-dione;-   (5R)-5-ethyl-3-[6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-2,4-dione;-   (5R)-5-ethyl-3-{6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione;-   (5R)-5-ethyl-3-{2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}-2,4-imidazolidinedione;-   (5R)-5-ethyl-5-methyl-3-[6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-2,4-dione;-   5,5-dimethyl-3-[6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-2,4-dione;

or a pharmaceutically acceptable salt thereof.

For the avoidance of doubt, the embodiments of any one feature of thecompounds of the invention may be combined with any embodiment ofanother feature of compounds of the invention to create a furtherembodiment.

It will be appreciated that for use in medicine the salts of thecompounds of formula (I) should be pharmaceutically acceptable. Suitablepharmaceutically acceptable salts will be apparent to those skilled inthe art. Pharmaceutically acceptable salts include those described byBerge, Bighley and Monkhouse J. Pharm. Sci. (1977) 66, pp 1-19. Suchpharmaceutically acceptable salts include acid addition salts formedwith inorganic acids e.g. hydrochloric, hydrobromic, sulphuric, nitricor phosphoric acid and organic acids e.g. succinic, maleic, acetic,fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonicor naphthalenesulfonic acid. Other salts e.g. oxalates or formates, maybe used, for example in the isolation of compounds of formula (I) andare included within the scope of this invention.

Certain of the compounds of formula (I) may form acid addition saltswith one or more equivalents of the acid. The present invention includeswithin its scope all possible stoichiometric and non-stoichiometricforms.

The compounds of formula (I) may be prepared in crystalline ornon-crystalline form and, if crystalline, may optionally be solvated,e.g. as the hydrate. This invention includes within its scopestoichiometric solvates (e.g. hydrates) as well as compounds containingvariable amounts of solvent (e.g. water).

It will be understood that the invention includes pharmaceuticallyacceptable derivatives of compounds of formula (I) and that these areincluded within the scope of the invention.

As used herein “pharmaceutically acceptable derivative” includes anypharmaceutically acceptable ester or salt of such ester of a compound offormula (I) which, upon administration to the recipient is capable ofproviding (directly or indirectly) a compound of formula (I) or anactive metabolite or residue thereof.

Suitably, a pharmaceutically acceptable prodrug is formed byfunctionalising the secondary nitrogen of the hydantoin, for examplewith a group “L” as illustrated below (wherein R represents dimethyl,methyl and ethyl, or ethyl—see formula (I)):

In one embodiment of the invention, a compound of formula (I) isfunctionalised via the secondary nitrogen of the hydantoin with a groupL, wherein L is selected from:

-   -   a) —PO(OH)O⁻.M⁺, wherein M⁺ is a pharmaceutically acceptable        monovalent counterion,    -   b) —PO(O⁻)₂.2M⁺,    -   c) —PO(O⁻)₂.D²⁺, wherein D²⁺ is a pharmaceutically acceptable        divalent counterion,    -   d) —CH(R^(X))—PO(OH)O⁻.M⁺, wherein R^(X) is hydrogen or C₁₋₃        alkyl,    -   e) —CH(R^(X))—PO(O⁻)₂.2M⁺,    -   f) —CH(R^(X))—PO(O⁻)₂.D²⁺    -   g) —SO₃ ⁻.M⁺,    -   h) —CH(R^(X))—SO₃ ⁻.M⁺, and    -   i) —CO—CH₂CH₂—CO₂.M⁺.

It is to be understood that the present invention encompasses allisomers of formula (I) and their pharmaceutically acceptablederivatives, including all geometric, tautomeric and optical forms, andmixtures thereof (e.g. racemic mixtures). Where additional chiralcentres are present in compounds of formula (I), the present inventionincludes within its scope all possible diastereoisomers, includingmixtures thereof. The different isomeric forms may be separated orresolved one from the other by conventional methods, or any given isomermay be obtained by conventional synthetic methods or by stereospecificor asymmetric syntheses.

The subject invention also includes isotopically-labelled compoundswhich are identical to those recited in formula (I) but for the factthat one or more atoms are replaced by an atom having an atomic mass ormass number different from the atomic mass or mass number most commonlyfound in nature. The skilled person will appreciate that in manycircumstances the proportion of an atom having an atomic mass or massnumber found less commonly in nature can also be been increased(referred to as “isotopic enrichment”). Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, fluorine, iodine and chlorine suchas ³H, ¹¹C, ¹⁴C, ¹⁸F, ¹²³I or ¹²⁵I. Another isotope of interest is ¹³C.Another isotope of interest is ²H (deuterium).

Compounds of the present invention and pharmaceutically acceptable saltsof said compounds that contain the aforementioned isotopes and/or otherisotopes of other atoms are within the scope of the present invention.Isotopically labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H or ¹⁴C have beenincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e. ³H, and carbon-14, i.e. ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.¹¹C and ¹⁸F isotopes are particularly useful in PET (positron emissiontomography).

Since the compounds of formula (I) are intended for use inpharmaceutical compositions it will readily be understood that they areeach preferably provided in substantially pure form, for example atleast 60% pure, more suitably at least 75% pure and preferably at least85%, especially at least 98% pure (% are on a weight for weight basis).Impure preparations of the compounds may be used for preparing the morepure forms used in the pharmaceutical compositions.

In general, the compounds of formula (I) may be made according to theorganic synthesis techniques known to those skilled in this field, aswell as by the representative methods set forth below, those in theExamples and modifications thereof.

Compounds of formula (I), and salts and solvates thereof, may beprepared by the general methods outlined in WO2012/076877.

The present invention provides compounds of formula (I) or apharmaceutically acceptable salt thereof for use in therapy.

The compounds of formula (I) or their pharmaceutically acceptable saltsmay be of use for the treatment or prophylaxis of a disease or disorderwhere a modulator of the Kv3.1 or Kv3.2 or Kv3.1 and Kv3.2 channels isrequired. As used herein, a modulator of Kv3.1 or Kv3.2 or Kv 3.1 andKv3.2 is a compound which alters the properties of these channels,either positively or negatively.

Compounds of the invention may be tested in the assay of BiologicalExample 1 to determine their modulatory properties.

In certain disorders it may be of benefit to utilise a modulator ofKv3.1 or Kv3.2 which demonstrates a particular selectivity profilebetween the two channels. For example a compound may be selective formodulation of Kv3.1 channels over modulation of Kv3.2 channelsdemonstrating, for example, at least a 2 fold, 5 fold or 10 foldactivity for Kv3.1 channels than for Kv3.2 channels. Alternatively, acompound may be selective for modulation of Kv3.2 channels overmodulation of Kv3.1 channels demonstrating, for example, at least a 2fold, 5 fold or 10 fold activity for Kv3.2 channels than for Kv3.1channels. In other cases a compound may demonstrate comparable activitybetween modulation of Kv3.1 and Kv3.2 channels, for example the activityfor each channel is less than 2 fold that for the other channel, such asless than 1.5 fold or less than 1.2 fold. The activity of a compound issuitably quantified by its potency as indicated by an EC50 value.

Diseases or conditions that may be mediated by modulation of Kv3.1and/or Kv3.2 channels may be selected from the list below. The numbersin brackets after the listed diseases below refer to the classificationcode in Diagnostic and Statistical Manual of Mental Disorders, 4thEdition, published by the American Psychiatric Association (DSM-IV)and/or the International Classification of Diseases, 10th Edition(ICD-10).

The compounds of formula (I) or their pharmaceutically acceptable saltsmay be of use for the treatment or prophylaxis of depression and mooddisorders including Major Depressive Episode, Manic Episode, MixedEpisode and Hypomanic Episode; Depressive Disorders including MajorDepressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder NotOtherwise Specified (311); Bipolar Disorders including Bipolar IDisorder, Bipolar II Disorder (Recurrent Major Depressive Episodes withHypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and BipolarDisorder Not Otherwise Specified (296.80); Other Mood Disordersincluding Mood Disorder Due to a General Medical Condition (293.83)which includes the subtypes With Depressive Features, With MajorDepressive-like Episode, With Manic Features and With Mixed Features),Substance-Induced Mood Disorder (including the subtypes With DepressiveFeatures, With Manic Features and With Mixed Features) and Mood DisorderNot Otherwise Specified (296.90); Seasonal affective disorder.

The compounds of formula (I) or their pharmaceutically acceptable saltsmay be of use for the treatment or prophylaxis of schizophreniaincluding the subtypes Paranoid Type (295.30), Disorganised Type(295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) andResidual Type (295.60); Schizophreniform Disorder (295.40);Schizoaffective Disorder (295.70) including the subtypes Bipolar Typeand Depressive Type; Delusional Disorder (297.1) including the subtypesErotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, SomaticType, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8);Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a GeneralMedical Condition including the subtypes With Delusions and WithHallucinations; Substance-Induced Psychotic Disorder including thesubtypes With Delusions (293.81) and With Hallucinations (293.82); andPsychotic Disorder Not Otherwise Specified (298.9).

The compounds of formula (I) or their pharmaceutically acceptable saltsmay be of use for the treatment or prophylaxis of anxiety disordersincluding Panic Attack; Panic Disorder including Panic Disorder withoutAgoraphobia (300.01) and Panic Disorder with Agoraphobia (300.21);Agoraphobia; Agoraphobia Without History of Panic Disorder (300.22),Specific Phobia (300.29, formerly Simple Phobia) including the subtypesAnimal Type, Natural Environment Type, Blood-Injection-Injury Type,Situational Type and Other Type), Social Phobia (Social AnxietyDisorder, 300.23), Obsessive-Compulsive Disorder (300.3), PosttraumaticStress Disorder (309.81), Acute Stress Disorder (308.3), GeneralizedAnxiety Disorder (300.02), Anxiety Disorder Due to a General MedicalCondition (293.84), Substance-Induced Anxiety Disorder, SeparationAnxiety Disorder (309.21), Adjustment Disorders with Anxiety (309.24)and Anxiety Disorder Not Otherwise Specified (300.00).

The compounds of formula (I) or their pharmaceutically acceptable saltsmay be of use for the treatment or prophylaxis of substance-relateddisorders including Substance Use Disorders such as SubstanceDependence, Substance Craving and Substance Abuse; Substance-InducedDisorders such as Substance Intoxication, Substance Withdrawal,Substance-Induced Delirium, Substance-Induced Persisting Dementia,Substance-Induced Persisting Amnestic Disorder, Substance-InducedPsychotic Disorder, Substance-Induced Mood Disorder, Substance-InducedAnxiety Disorder, Substance-Induced Sexual Dysfunction,Substance-Induced Sleep Disorder and Hallucinogen Persisting PerceptionDisorder (Flashbacks); Alcohol-Related Disorders such as AlcoholDependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication(303.00), Alcohol Withdrawal (291.81), Alcohol Intoxication Delirium,Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia,Alcohol-Induced Persisting Amnestic Disorder, Alcohol-Induced PsychoticDisorder, Alcohol-Induced Mood Disorder, Alcohol-Induced AnxietyDisorder, Alcohol-Induced Sexual Dysfunction, Alcohol-Induced SleepDisorder and Alcohol-Related Disorder Not Otherwise Specified (291.9);Amphetamine (or Amphetamine-Like)-Related Disorders such as AmphetamineDependence (304.40), Amphetamine Abuse (305.70), AmphetamineIntoxication (292.89), Amphetamine Withdrawal (292.0), AmphetamineIntoxication Delirium, Amphetamine Induced Psychotic Disorder,Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder,Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced SleepDisorder and Amphetamine-Related Disorder Not Otherwise Specified(292.9); Caffeine Related Disorders such as Caffeine Intoxication(305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced SleepDisorder and Caffeine-Related Disorder Not Otherwise Specified (292.9);Cannabis-Related Disorders such as Cannabis Dependence (304.30),Cannabis Abuse (305.20), Cannabis Intoxication (292.89), CannabisIntoxication Delirium, Cannabis-Induced Psychotic Disorder,Cannabis-Induced Anxiety Disorder and Cannabis-Related Disorder NotOtherwise Specified (292.9); Cocaine-Related Disorders such as CocaineDependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication(292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium,Cocaine-Induced Psychotic Disorder, Cocaine-Induced Mood Disorder,Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction,Cocaine-Induced Sleep Disorder and Cocaine-Related Disorder NotOtherwise Specified (292.9); Hallucinogen-Related Disorders such asHallucinogen Dependence (304.50), Hallucinogen Abuse (305.30),Hallucinogen Intoxication (292.89), Hallucinogen Persisting PerceptionDisorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium,Hallucinogen-Induced Psychotic Disorder, Hallucinogen-Induced MoodDisorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-RelatedDisorder Not Otherwise Specified (292.9); Inhalant-Related Disorderssuch as Inhalant Dependence (304.60), Inhalant Abuse (305.90), InhalantIntoxication (292.89), Inhalant Intoxication Delirium, Inhalant-InducedPersisting Dementia, Inhalant-Induced Psychotic Disorder,Inhalant-Induced Mood Disorder, Inhalant-Induced Anxiety Disorder andInhalant-Related Disorder Not Otherwise Specified (292.9);Nicotine-Related Disorders such as Nicotine Dependence (305.1), NicotineWithdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified(292.9); Opioid-Related Disorders such as Opioid Dependence (304.00),Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal(292.0), Opioid Intoxication Delirium, Opioid-Induced PsychoticDisorder, Opioid-Induced Mood Disorder, Opioid-Induced SexualDysfunction, Opioid-Induced Sleep Disorder and Opioid-Related DisorderNot Otherwise Specified (292.9); Phencyclidine (orPhencyclidine-Like)-Related Disorders such as Phencyclidine Dependence(304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication(292.89), Phencyclidine Intoxication Delirium, Phencyclidine-InducedPsychotic Disorder, Phencyclidine-Induced Mood Disorder,Phencyclidine-Induced Anxiety Disorder and Phencyclidine-RelatedDisorder Not Otherwise Specified (292.9); Sedative-, Hypnotic-, orAnxiolytic-Related Disorders such as Sedative, Hypnotic, or AnxiolyticDependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40),Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative,Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, orAnxiolytic Intoxication Delirium, Sedative, Hypnotic, or AnxiolyticWithdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-PersistingDementia, Sedative-, Hypnotic-, or Anxiolytic-Persisting AmnesticDisorder, Sedative-, Hypnotic-, or Anxiolytic-Induced PsychoticDisorder, Sedative-, Hypnotic-, or Anxiolytic-Induced Mood Disorder,Sedative-, Hypnotic-, or Anxiolytic-Induced Anxiety Disorder Sedative-,Hypnotic-, or Anxiolytic-Induced Sexual Dysfunction, Sedative-,Hypnotic-, or Anxiolytic-Induced Sleep Disorder and Sedative-,Hypnotic-, or Anxiolytic-Related Disorder Not Otherwise Specified(292.9); Polysubstance-Related Disorder such as Polysubstance Dependence(304.80); and Other (or Unknown) Substance-Related Disorders such asAnabolic Steroids, Nitrate Inhalants and Nitrous Oxide.

The compounds of formula (I) or their pharmaceutically acceptable saltsmay be of use for the enhancement of cognition including the treatmentof cognition impairment in other diseases such as schizophrenia, bipolardisorder, depression, other psychiatric disorders and psychoticconditions associated with cognitive impairment, e.g. Alzheimer'sdisease. Alternatively, the compounds of formula (I) or theirpharmaceutically acceptable salts and/or solvates may be of use for theprophylaxis of cognition impairment, such as may be associated withdiseases such as schizophrenia, bipolar disorder, depression, otherpsychiatric disorders and psychotic conditions associated with cognitiveimpairment, e.g. Alzheimer's disease.

The compounds of formula (I) or their pharmaceutically acceptable saltsmay be of use for the treatment or prophylaxis of sleep disordersincluding primary sleep disorders such as Dyssomnias such as PrimaryInsomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347),Breathing-Related Sleep Disorders (780.59), Circadian Rhythm SleepDisorder (307.45) and Dyssomnia Not Otherwise Specified (307.47);primary sleep disorders such as Parasomnias such as Nightmare Disorder(307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46)and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Relatedto Another Mental Disorder such as Insomnia Related to Another MentalDisorder (307.42) and Hypersomnia Related to Another Mental Disorder(307.44); Sleep Disorder Due to a General Medical Condition, inparticular sleep disturbances associated with such diseases asneurological disorders, neuropathic pain, restless leg syndrome, heartand lung diseases; and Substance-Induced Sleep Disorder including thesubtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and MixedType; sleep apnea and jet-lag syndrome.

The compounds of formula (I) or their pharmaceutically acceptable saltsmay be of use for the treatment or prophylaxis of eating disorders suchas Anorexia Nervosa (307.1) including the subtypes Restricting Type andBinge-Eating/Purging Type; Bulimia Nervosa (307.51) including thesubtypes Purging Type and Nonpurging Type; Obesity; Compulsive EatingDisorder; Binge Eating Disorder; and Eating Disorder Not OtherwiseSpecified (307.50).

The compounds of formula (I) or their pharmaceutically acceptable saltsmay be of use for the treatment or prophylaxis of Autism SpectrumDisorders including Autistic Disorder (299.00), Asperger's Disorder(299.80), Rett's Disorder (299.80), Childhood Disintegrative Disorder(299.10) and Pervasive Disorder Not Otherwise Specified (299.80,including Atypical Autism).

The compounds of formula (I) or their pharmaceutically acceptable saltsmay be of use for the treatment or prophylaxis ofAttention-Deficit/Hyperactivity Disorder including the subtypesAttention-Deficit/Hyperactivity Disorder Combined Type (314.01),Attention-Deficit/Hyperactivity Disorder Predominantly Inattentive Type(314.00), Attention-Deficit/Hyperactivity Disorder Hyperactive-ImpulseType (314.01) and Attention-Deficit/Hyperactivity Disorder Not OtherwiseSpecified (314.9); Hyperkinetic Disorder; Disruptive Behaviour Disorderssuch as Conduct Disorder including the subtypes childhood-onset type(321.81), Adolescent-Onset Type (312.82) and Unspecified Onset (312.89),Oppositional Defiant Disorder (313.81) and Disruptive Behaviour DisorderNot Otherwise Specified; and Tic Disorders such as Tourette's Disorder(307.23).

The compounds of formula (I) or their pharmaceutically acceptable saltsmay be of use for the treatment or prophylaxis of Personality Disordersincluding the subtypes Paranoid Personality Disorder (301.0), SchizoidPersonality Disorder (301.20), Schizotypal Personality Disorder(301,22), Antisocial Personality Disorder (301.7), BorderlinePersonality Disorder (301,83), Histrionic Personality Disorder (301.50),Narcissistic Personality Disorder (301,81), Avoidant PersonalityDisorder (301.82), Dependent Personality Disorder (301.6),Obsessive-Compulsive Personality Disorder (301.4) and PersonalityDisorder Not Otherwise Specified (301.9).

The compounds of formula (I) or their pharmaceutically acceptable saltsmay be of use for the treatment or prophylaxis of Sexual dysfunctionsincluding Sexual Desire Disorders such as Hypoactive Sexual DesireDisorder (302.71), and Sexual Aversion Disorder (302.79); sexual arousaldisorders such as Female Sexual Arousal Disorder (302.72) and MaleErectile Disorder (302.72); orgasmic disorders such as Female OrgasmicDisorder (302.73), Male Orgasmic Disorder (302.74) and PrematureEjaculation (302.75); sexual pain disorder such as Dyspareunia (302.76)and Vaginismus (306.51); Sexual Dysfunction Not Otherwise Specified(302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81),Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism (302.83),Sexual Sadism (302.84), Transvestic Fetishism (302.3), Voyeurism(302.82) and Paraphilia Not Otherwise Specified (302.9); gender identitydisorders such as Gender Identity Disorder in Children (302.6) andGender Identity Disorder in Adolescents or Adults (302.85); and SexualDisorder Not Otherwise Specified (302.9).

The compounds of formula (I) or their pharmaceutically acceptable saltsmay be of use for the treatment or prophylaxis of Impulse controldisorder including: Intermittent Explosive Disorder (312.34),Kleptomania (312.32), Pathological Gambling (312.31), Pyromania(312.33), Trichotillomania (312.39), Impulse-Control Disorders NotOtherwise Specified (312.3), Binge Eating, Compulsive Buying, CompulsiveSexual Behaviour and Compulsive Hoarding.

The compounds of formula (I) or their pharmaceutically acceptable saltsmay be of use for the treatment or prophylaxis of hearing disordersincluding auditory neuropathy, auditory processing disorder, hearingloss, which includes sudden hearing loss, noise induced hearing loss,substance-induced hearing loss, and hearing loss in adults over 60(presbycusis), and tinnitus.

The compounds of formula (I) or their pharmaceutically acceptable saltsmay be of use for the treatment or prophylaxis of Ménière's disease,disorders of balance, and disorders of the inner ear.

The compounds of formula (I) or their pharmaceutically acceptable saltsmay be of use for the treatment or prophylaxis of hyperacusis anddisturbances of loudness perception, including Fragile-X syndrome andautism.

The compounds of formula (I) or their pharmaceutically acceptable saltsmay be of use for the treatment or prophylaxis of Epilepsy, (including,but not limited to, localization-related epilepsies, generalizedepilepsies, epilepsies with both generalized and local seizures, and thelike), seizures associated with Lennox-Gastaut syndrome, seizures as acomplication of a disease or condition (such as seizures associated withencephalopathy, phenylketonuria, juvenile Gaucher's disease, Lundborg'sprogressive myoclonic epilepsy, stroke, head trauma, stress, hormonalchanges, drug use or withdrawal, alcohol use or withdrawal, sleepdeprivation, fever, infection, and the like), essential tremor, restlesslimb syndrome, partial and generalised seizures (including tonic,clonic, tonic-clonic, atonic, myoclonic, absence seizures), secondarilygeneralized seizures, temporal lobe epilepsy, absence epilepsies(including childhood, juvenile, myoclonic, photo- and pattern-induced),severe epileptic encephalopathies (including hypoxia-related andRasmussen's syndrome), febrile convulsions, epilepsy partialis continua,progressive myoclonus epilepsies (including Unverricht-Lundborg diseaseand Lafora's disease), post-traumatic seizures/epilepsy including thoserelated to head injury, simple reflex epilepsies (includingphotosensive, somatosensory and proprioceptive, audiogenic andvestibular), metabolic disorders commonly associated with epilepsy suchas pyridoxine-dependent epilepsy, Menkes' kinky hair disease, Krabbe'sdisease, epilepsy due to alcohol and drug abuse (e.g. cocaine), corticalmalformations associated with epilepsy (e.g. double cortex syndrome orsubcortical band heterotopia), chromosomal anomolies associated withseizures or epilepsy such as Partial monosomy (15Q)/Angelman syndrome.

In one embodiment of the invention, there is provided a compound offormula (I) or a pharmaceutically acceptable salt thereof for thetreatment or prophylaxis of depression and mood disorders, hearingdisorders, schizophrenia, substance abuse disorders, sleep disorders orepilepsy.

In one embodiment of the invention, there is provided a compound offormula (I) or a pharmaceutically acceptable salt thereof for thetreatment or prophylaxis of bipolar disorder or mania.

In one embodiment of the invention, there is provided a compound offormula (I) or a pharmaceutically acceptable salt and/or solvate thereoffor the treatment or prophylaxis of ataxia, such as spinocerebellarataxia.

In one embodiment of the invention, there is provided a compound offormula (I) or a pharmaceutically acceptable salt and/or solvate thereoffor the treatment or prophylaxis of cognition impairment.

The term “treatment” or “treating” as used herein includes the control,mitigation, reduction, or modulation of the disease state or itssymptoms.

The term “prophylaxis” is used herein to mean preventing symptoms of adisease or disorder in a subject or preventing recurrence of symptoms ofa disease or disorder in an afflicted subject and is not limited tocomplete prevention of an affliction.

The invention also provides a method of treating or preventing a diseaseor disorder where a modulator of Kv3 is required, for example thosediseases and disorders mentioned hereinabove, which comprisesadministering to a subject in need thereof an effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

The invention also provides a compound of formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment orprophylaxis of a disease or disorder where a modulator of Kv3 isrequired, for example those diseases and disorders mentionedhereinabove.

The invention also provides the use of a compound of formula (I), or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment or prophylaxis of a disease or disorderwhere a modulator of Kv3 is required, for example those diseases anddisorders mentioned hereinabove.

The invention also provides a method of treating depression and mooddisorders, schizophrenia, substance abuse disorders, sleep disorders orepilepsy, for example for those indications mentioned hereinabove, whichcomprises administering to a subject in need thereof an effective amountof a Kv3 modulator or a pharmaceutically acceptable salt thereof.

For use in therapy the compounds of the invention are usuallyadministered as a pharmaceutical composition. The invention alsoprovides a pharmaceutical composition comprising a compound of formula(I), or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

The compounds of formula (I) or their pharmaceutically acceptable saltsmay be administered by any convenient method, e.g. by oral, parenteral,buccal, sublingual, nasal, rectal or transdermal administration, and thepharmaceutical compositions adapted accordingly. Other possible routesof administration include intratympanic and intracochlear.

The compounds of formula (I) or their pharmaceutically acceptable saltswhich are active when given orally can be formulated as liquids orsolids, e.g. as syrups, suspensions, emulsions, tablets, capsules orlozenges.

A liquid formulation will generally consist of a suspension or solutionof the active ingredient in a suitable liquid carrier(s) e.g. an aqueoussolvent such as water, ethanol or glycerine, or a non-aqueous solvent,such as polyethylene glycol or an oil. The formulation may also containa suspending agent, preservative, flavouring and/or colouring agent.

A composition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidformulations, such as magnesium stearate, starch, lactose, sucrose andcellulose.

A composition in the form of a capsule can be prepared using routineencapsulation procedures, e.g. pellets containing the active ingredientcan be prepared using standard carriers and then filled into a hardgelatin capsule; alternatively a dispersion or suspension can beprepared using any suitable pharmaceutical carrier(s), e.g. aqueousgums, celluloses, silicates or oils and the dispersion or suspensionthen filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension ofthe active ingredient in a sterile aqueous carrier or parenterallyacceptable oil, e.g. polyethylene glycol, polyvinyl pyrrolidone,lecithin, arachis oil or sesame oil. Alternatively, the solution can belyophilised and then reconstituted with a suitable solvent just prior toadministration.

Compositions for nasal administration may conveniently be formulated asaerosols, drops, gels and powders. Aerosol formulations typicallycomprise a solution or fine suspension of the active ingredient in apharmaceutically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container which can take the form of a cartridge or refill foruse with an atomising device. Alternatively the sealed container may bea disposable dispensing device such as a single dose nasal inhaler or anaerosol dispenser fitted with a metering valve. Where the dosage formcomprises an aerosol dispenser, it will contain a propellant which canbe a compressed gas e.g. air, or an organic propellant such as afluorochlorohydrocarbon or hydrofluorocarbon. Aerosol dosage forms canalso take the form of pump-atomisers.

Compositions suitable for buccal or sublingual administration includetablets, lozenges and pastilles where the active ingredient isformulated with a carrier such as sugar and acacia, tragacanth, orgelatin and glycerin.

Compositions for rectal administration are conveniently in the form ofsuppositories containing a conventional suppository base such as cocoabutter.

Compositions suitable for transdermal administration include ointments,gels and patches.

In one embodiment the composition is in unit dose form such as a tablet,capsule or ampoule.

The composition may contain from 0.1% to 100% by weight, for examplefrom 10 to 60% by weight, of the active material, depending on themethod of administration. The composition may contain from 0% to 99% byweight, for example 40% to 90% by weight, of the carrier, depending onthe method of administration. The composition may contain from 0.05 mgto 1000 mg, for example from 1.0 mg to 500 mg, of the active material,depending on the method of administration. The composition may containfrom 50 mg to 1000 mg, for example from 100 mg to 400 mg of the carrier,depending on the method of administration. The dose of the compound usedin the treatment of the aforementioned disorders will vary in the usualway with the seriousness of the disorders, the weight of the sufferer,and other similar factors. However, as a general guide suitable unitdoses may be 0.05 to 1000 mg, more suitably 1.0 to 500 mg, and such unitdoses may be administered more than once a day, for example two or threea day. Such therapy may extend for a number of weeks or months.

The invention provides, in a further aspect, a combination comprising acompound of formula (I) or a pharmaceutically acceptable derivativethereof together with a further therapeutic agent or agents.

The invention provides a compound of formula (I), for use in combinationwith a further therapeutic agent or agents.

When the compounds are used in combination with other therapeuticagents, the compounds may be administered either sequentially orsimultaneously by any convenient route.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with apharmaceutically acceptable carrier or excipient comprise a furtheraspect of the invention. The individual components of such combinationsmay be administered either sequentially or simultaneously in separate orcombined pharmaceutical formulations. The individual components ofcombinations may also be administered separately, through the same ordifferent routes.

When a compound of formula (I) or a pharmaceutically acceptablederivative thereof is used in combination with a second therapeuticagent active against the same disease state the dose of each compoundmay differ from that when the compound is used alone. Appropriate doseswill be readily appreciated by those skilled in the art.

A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient temperature and atmospheric pressure, isusually adapted for oral, parenteral or rectal administration and, assuch, may be in the form of tablets, capsules, oral liquid preparations,powders, granules, lozenges, reconstitutable powders, injectable orinfusible solutions or suspensions or suppositories. Orallyadministrable compositions are generally preferred.

Furthermore, the invention relates to a method for manufacturingcompounds of formula (I), to novel intermediates of use in themanufacture of compounds of formula (I) and to the manufacture of suchintermediates.

Particular intermediates of interest include:

-   7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-ol (Intermediate    13)

and

-   3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-ol (Intermediate 27)

and

-   2,2-difluoro-7-methyl-1,3-benzodioxol-4-ol (Intermediate 37)

Other intermediates of interest are the anilides:

-   6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyridin-3-amine    (Intermediate 15)

and

-   2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-amine    (Intermediate 19)

and

-   6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinamine    (Intermediate 29)

and

-   2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinamine    (Intermediate 33)

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention is illustrated, by way of example only, withreference to the following figures in which:

FIG. 1a hKv3.2 currents recorded using the assay described in BiologicalExample 1. Data shown are the individual currents over the period of thedepolarising voltage step to −15 mV recorded from 4 different cells attwo concentrations of the compound of Reference Example RE1. The dataare fitted by a single exponential curve (solid lines) using the fittingprocedure in Prism version 5 (Graphpad Software Inc).

FIG. 1b hKv3.2 currents recorded using the assay described in BiologicalExample 1. Data shown are the individual currents over the period of thedepolarising voltage step to −15 mV recorded from 2 different cells attwo concentrations of compound of Reference Example RE3. The data arefitted by a single exponential curve (solid lines) using the fittingprocedure in Prism version 5 (Graphpad Software Inc).

FIG. 2 Recordings made from identified “fast-firing” interneurons in thesomatosensory cortex of the mouse.

EXPERIMENTAL

The invention is illustrated by the compounds described below. Thefollowing examples describe the laboratory synthesis of specificcompounds of the invention and are not meant to limit the scope of theinvention in any way with respect to compounds or processes. It isunderstood that, although specific reagents, solvents, temperatures andtime periods are used, there are many possible equivalent alternativesthat can be used to produce similar results. This invention is meant toinclude such equivalents.

Analytical Equipment

Starting materials, reagents and solvents were obtained from commercialsuppliers and used without further purification unless otherwise stated.Unless otherwise stated, all compounds with chiral centres are racemic.Where reactions are described as having been carried out in a similarmanner to earlier, more completely described reactions, the generalreaction conditions used were essentially the same. Work up conditionsused were of the types standard in the art, but may have been adaptedfrom one reaction to another. The starting material may not necessarilyhave been prepared from the batch referred to. Compounds synthesised mayhave various purities ranging from for example 85% to 98%. Calculationsof number of moles and yield are in some cases adjusted for this.

Nuclear Magnetic Resonance (NMR) spectra (¹H; ¹³C and ¹³F) were recordedeither on Varian instruments at 300, 400, 500 or 600 MHz, or on Brukerinstruments at 400 MHz. Chemical shifts are reported in ppm (δ) usingthe residual solvent line as internal standard. Splitting patterns aredesigned as s (singlet), br.s (broad singlet), d (doublet), t (triplet),q (quartet), dd (doublet of doublets), dt (doublet of triplets) and m(multiplet). The NMR spectra were recorded at temperatures ranging from25 to 30° C.

Direct infusion Mass spectra (MS) were run on a mass spectrometer,operating in ES (+) and ES (−) ionization mode coupled with an HPLCinstrument Agilent 1100 Series [LC/MS-ESI(+) analyses were performed ona Supelcosil ABZ+Plus (33×4.6 mm, 3 μm) (mobile phase: from10%[CH₃CN+0.05% TFA] to 90%[CH₃CN+0.05% TFA] and 10% [water] in 2.2 min,under these conditions for 2.8 min. T=45° C., flux=0.9 mL/min)]. The useof this methodology is indicated by “MS_2 (ESI)” in the analyticcharacterization of the described compounds.

Quality Control:

LC/MS-ES+ under acidic conditions was performed on a Zorbax SB C18column (1.8 μm 3×50 mm). Mobile phase: A: (H2O+0.05% TFA by vol.)/B:(CH3CN+0.05% TFA by vol). Gradient: t=0 min 0% (B), from 0 to 95% (B) in2.5 min, 95% (B) for 0.2 min, from 95 to 100% (B) in 0.2 min, 100% (B)for 0.4 min, From 100% to 0% (B) in 0.1 min. Stop time 4 min. ColumnT=60° C. Flow rate: 1.5 ml/min. Mass range ES+: (100-1000 amu, F=60). UVdetection wavelengths: DAD 1A=220.8, DAD 1B=254.8. The use of thismethodology is indicated by “LC/MS: QC_3_MIN” in the analyticcharacterization of the described compounds.

Ultra Performance Liquid Chromatography with an Acidic Gradient:

Total ion current (TIC) and DAD UV chromatographic traces together withMS and UV spectra associated with the peaks were taken on a UPLC/MSAcquity™ system equipped with 2996 PDA detector and coupled to a WatersMicromass ZQ™ mass spectrometer operating in positive or negativeelectrospray ionisation mode [LC/MS−ES (+ or −): analyses were performedusing an Acquity™ UPLC BEH C18 column (50×2.1 mm, 1.7 μm particle size).General Method: Mobile phase: A: (water+0.1% HCO2H)/B: (CH3CN+0.06%HCO2H). Gradient: t=0 min 3% (B), t=0.05 min 6% (B), t=0.57 min 70% (B),t=1.06 min 99% (B) lasting for 0.389 min, t=1.45 min 3% (B), stop time1.5 min. Column T=40° C. Flow rate=1.0 mL/min. Mass range: ES (+):100-1000 amu. ES (−): 100-800 amu. UV detection range: 210-350 nm. Theuse of this methodology is indicated by “UPLC” in the analyticcharacterization of the described compounds.

Ultra Performance Liquid Chromatography with a Basic Gradient:

Total ion current (TIC) and DAD UV chromatographic traces together withMS and UV spectra associated with the peaks were taken on a UPLC/MSAcquity™ system equipped with PDA detector and coupled to a Waters SQDmass spectrometer operating in positive and negative alternateelectrospray ionisation mode [LC/MS−ES+/−: analyses were performed usingan Acquity™ UPLC BEH C18 column (50×2.1 mm, 1.7 μm particle size).Mobile phase: A: (10 mM aqueous solution of NH4HCO3 (adjusted to pH 10with ammonia))/B: CH3CN. Gradient: t=0 min 3% (B), t=1.06 min 99% (B)lasting for 0.39 min, t=1.46 min 3% (B), stop time 1.5 min. Column T=40°C. Flow rate=1.0 mL/min. Mass range: ES (+): 100-1000 amu. ES (−):100-1000 amu. UV detection range: 220-350 nm. The use of thismethodology is indicated by “UPLC_B” in the analytic characterization ofthe described compounds.

In a number of preparations, purification was performed using Biotageautomatic flash chromatography (SP1 and SP4) or Flash Master Personalsystems.

Flash chromatographies were carried out on silica gel 230-400 mesh(supplied by Merck AG Darmstadt, Germany) or on silica gel 300-400 mesh(supplied by Sinopharm Chemical Reagent Co., Ltd.), Varian Mega Be—Sipre-packed cartridges, pre-packed Biotage silica cartridges (e.g.Biotage SNAP cartridge).

Abbreviations

-   AIBN azobisisobutyronitrile-   BuLi butyllithium-   CDCl₃ deutrated chloroform-   CCl₄ carbon tetrachloride-   D₂O deutrated water-   DCM dichloromethane-   DIAD Diisopropyl azodicarboxylate-   DIPEA N,N-diisopropylethylamine-   DMAP 4-dimethylaminopyridine-   DMF N,N-dimethylformamide-   DMSO dimethylsulfoxide-   DMSO-d₆ deutrated dimethylsulfoxide-   Et₂O diethyl ether-   EtOAc ethyl acetate-   EtOH ethanol-   h hours-   H₂O₂ Hydrogen peroxide-   HATU    (O-7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro    phosphate)-   HCO2H formic acid-   HCl hydrogen chloride-   K₂CO₃ potassium carbonate-   KHMDS potassium hexamethyldisilazide-   KOH potassium hydroxide-   LiAlH₄ Lithium aluminum hydride-   MeCN/CH₃CN acetonitrile-   MeOH methanol-   MDAP mass-directed autopurification-   MOM methoxymethyl-   MOM-Cl chloromethyl methyl ether-   NaH sodium hydride-   Na₂SO₄ sodium sulphate-   NBS N-Bromosuccinimide-   Na₂CO₃ sodium carbonate-   NaOH sodium hydroxide-   NaOMe sodium methoxide-   NH₄OH ammonium hydroxide-   NH4HCO3H ammonium bicarbonate-   NMR Nuclear Magnetic Resonance-   Pd/C palladium on charcoal-   PE petroleum ether-   r.t. room temperature-   sec-Bu Li sec-Butyllithium-   SCRC Sinopharm Chemical Reagent Co., Ltd-   T3P propylphosphonic anhydride-   TBAF Tetrabutylammonium fluoride-   TBME Methyl tert-butyl ether-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran

Intermediate 1 1-(methyloxy)-3-{[(methyloxy)methyl]oxy}benzene

To a solution of 3-(methyloxy)phenol (10.38 g, 84 mmol) intetrahydrofurane (100 ml, SCRC) was added NaH (60% wt., 1.824 g, 76mmol, Aldrich) portionwise under ice-cooling. The reaction mixture wasstirred at room temperature for 1 hour and bromomethyl methyl ether (9.5g, 76 mmol, SCRC) was then added. The resulting mixture was stirred atroom temperature for 2 hours and water (50 ml) was added. The reactionmixture was extracted with ethyl acetate (2 times 50 ml, SCRC) and thecombined organic layers were dried over sodium sulphate, evaporated. Theresidue was purified by column chromatography on silica gel(EtOAc:PE=1:100) to afford the title compound (10.2 g) as a colorlessliquid.

Intermediate 2 2-iodo-1-(methyloxy)-3-{[(methyloxy)methyl]oxy}benzene

To a solution of 1-(methyloxy)-3-{[(methyloxy)methyl]oxy}benzene(Intermediate 1, 10 g, 59.5 mmol) in tetrahydrofurane (100 ml, SCRC)precooled to −78° C. was added dropwise BuLi (2.5 M in THF, 28.5 ml,71.3 mmol, SCRC), maintaining the inner temperature lower than −70° C.After the addition was complete, the mixture was stirred at −70° C. for2 hours and a solution of iodine (15.09 g, 59.5 mmol, SCRC) in THF (50ml, SCRC) was added dropwise. The resulting mixture was stirred for 2hours at room temperature and quenched with a saturated aqueous solutionof ammonium chloride (100 ml). The mixture was extracted with ethylacetate (3 times 300 ml, SCRC) and the combined organic layers weredried, evaporated and purified by silica gel chromatography with aseluents EtOAc: PE (1/100) to afford the title compound (16.2 g) as ayellow liquid.

Intermediate 3 2-iodo-3-(methyloxy)phenol

To a solution of 2-iodo-1-(methyloxy)-3-{[(methyloxy)methyl]oxy}benzene(Intermediate 2, 16.2 g, 55.1 mmol) in dichloromethane (100 ml, SCRC)was bubbled HCl (g) for 30 mins. TLC showed that the reaction wascompleted. The reaction mixture was poured into an aqueous saturatedsolution of NaHCO₃ (200 ml) and extracted with dichloromethane (3×200ml, SCRC). The combined organic layers were dried, evaporated andpurified by column chromatography on silica gel (EtOAc:PE=1:50) toafford the title compound as a yellow liquid (10.3 g).

Intermediate 42-iodo-1-(methyloxy)-3-[(2-methyl-2-propen-1-yl)oxy]benzene

To a solution of 2-iodo-3-(methyloxy)phenol (Intermediate 3, 10.3 g) inDMF (100 ml, SCRC) was added NaH (60%, wt., 1.977 g, 49.4 mmol)portionwise. The reaction mixture was stirred at room temperature for 1hour and 3-chloro-2-methyl-1-propene (3.73 g, 41.2 mmol, Aldrich) wasadded. The resulting mixture was stirred at room temperature for 2 hoursand water (50 ml) was added. The reaction mixture was extracted withethyl acetate (3 times 200 ml, SCRC) and the combined organic layer weredried, evaporated and purified by silica gel chromatography with aseluents EtOAc/PE (1/30) to afford the title compound as a yellow liquid(11.6 g)

¹H-NMR (400 MHz, CDCl₃) δ ppm: 7.25 (1H, t), 6.52-6.47 (2H, m), 5.21(1H, s), 5.01 (1H, s), 4.49 (2H, s), 3.89 (3H, s), 1.87 (3H, s)

Intermediate 5 3,3-dimethyl-4-(methyloxy)-2,3-dihydro-1-benzofuran

To a solution of2-iodo-1-(methyloxy)-3-[(2-methyl-2-propen-1-yl)oxy]benzene(Intermediate 4, 6.08 g) in toluene (50 ml, SCRC) were added AIBN (3.61g, 21.99 mmol, SCRC) and tributylstannane (11.60 g, 40.0 mmol, Aldrich).The reaction mixture was heated at reflux for 3 hours and then cooled toroom temperature. Water (100 ml) was added and the mixture was extractedwith ethyl acetate (3 times 200 ml, SCRC). The combined organic layerswere dried, evaporated and purified by silica gel chromatography with aseluents EtOAc/PE (1/50) to afford the title compound as a yellow liquid(2.7 g).

¹H-NMR (400 MHz, DMSO-d₆) δ ppm: 7.05 (1H, t), 6.50 (1H, d), 6.39 (1H,d), 4.14 (2H, s), 3.77 (3H, s), 1.34 (6H, s);

Intermediate 6 3,3-dimethyl-2,3-dihydro-1-benzofuran-4-ol

To a solution of 3,3-dimethyl-4-(methyloxy)-2,3-dihydro-1-benzofuran(Intermediate 5, 4.0 g) in dichloromethane (100 ml, SCRC) was added BBr3(6.37 ml, 67.3 mmol, SCRC) dropwise under ice-cooling. After theaddition was complete, the reaction mixture was stirred for 2 hours atroom temperature and then water (20 ml) was added. The resulting mixturewas extracted with ethyl acetate (3 times 100 ml, SCRC) and the combinedorganic layers were dried, evaporated and purified by silica gelchromatography with EtOAc/PE as eluents (1/20) to afford the titlecompound (2.8 g).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 6.98-6.94 (1H, t), 6.41-6.39 (1H, dd),6.25-6.23 (1H, dd), 4.21 (2H, s), 1.45 (6H, s); MS_2: 163 [M−H]−.

Intermediate 7 2,4-bis(methoxymethoxy)-1-methyl-benzene

To a solution of 4-methylbenzene-1,3-diol (4 g, 32.26 mmol) in dryN,N-Dimethylformamide (30 ml) at 0° C. sodium hydride (60% dispersion inmineral oil) (3.87 g, 96.78 mmol) was added and the reaction mixture wasstirred for 15 minutes at the same temperature. MOM-Cl (7.35 ml, 96.78mmol) was quickly added and the reaction mixture was stirred for 1 hourwhile the temperature was allowed to reach room temperature. Thereaction was quenched with brine (40 ml) and extracted with ethylacetate (3×80 ml). The organic layer was washed with ice cold brine(2×50 ml), dried over sodium sulphate, filtered and evaporated and theresidue was purified by flash chromatography (Biotage system) on silicagel using a 100 g SNAP column and cyclohexane to cyclohexane/ethylacetate 8:2 as eluents affording the title compound (6.1 g) as acolourless oil.

LC/MS: QC_3_MIN: Rt=1.811 min; 213 [M+H]+.

Intermediate 8 ethyl2-[2,6-bis(methoxymethoxy)-3-methyl-phenyl]-2-oxo-acetate

To a solution of 2,4-bis(methoxymethoxy)-1-methyl-benzene (Intermediate7, 5.5 g, 25.94 mmol) in dry tetrahydrofuran (50 ml) at room temperatureBuLi 1.6M in hexane (19.45 ml, 31.13 mmol) was added and the reactionmixture was stirred for 30 minutes at the same temperature. The mixturewas cooled to −78° C. and it was added (via cannulation) to a solutionof ethyl chlorooxoacetate (4.35 ml, 38.9 mmol) in dry tetrahydrofuran(30 ml) at −78° C. The reaction mixture was stirred at −78° C. for 30minutes. The reaction was quenched with water (20 ml), diluted withbrine (50 ml) and extracted with ethyl acetate (2×100 ml). Combinedorganic layers were dried over sodium sulphate, filtered and evaporated.The residue was purified by flash chromatography (Biotage system) onsilica gel using a 100 g SNAP column and cyclohexane tocyclohexane/ethyl acetate 8:2 as eluent affording the title compound(4.65 g) as a light yellow oil.

LC/MS: QC_3_MIN: Rt=1.865 min.

Intermediate 9 ethyl2-[2,6-bis(methoxymethoxy)-3-methyl-phenyl]prop-2-enoate

To a suspension of methyltriphenylphosphonium bromide (8.78 g, 24.6mmol) in dry tetrahydrofuran (50 ml) at 0° C. KHMDS 0.5M solution intoluene (44.22 ml, 22.11 mmol) was slowly added and the reaction mixturewas stirred for 15 minutes at 0° C. and for 45 minutes at roomtemperature. The reaction mixture was cooled to 0° C. and it was slowlyadded to a solution of ethyl2-[2,6-bis(methoxymethoxy)-3-methyl-phenyl]-2-oxo-acetate (Intermediate8, 4.6 g, 14.74 mmol) in dry tetrahydrofuran (25 mL) at 0° C. and thereaction mixture was stirred for 2 hours at 0° C. The reaction wasquenched with water (50 ml), diluted with brine (50 ml) and extractedwith ethyl acetate (2×100 ml). The organic layer was dried over sodiumsulphate, filtered and evaporated. The residue was purified by flashchromatography (Biotage system) on silica gel using a 100 g SNAP columnand cyclohexane to cyclohexane/ethyl acetate 8:2 as eluents affordingthe title compound (3.8 g) as a colourless oil.

LC/MS: QC_3_MIN: Rt=1.930 min.

Intermediate 10 ethyl1-[2,6-bis(methoxymethoxy)-3-methyl-phenyl]cyclopropanecarboxylate

To a solution of trimethylsulfoxonium iodide (4.4 g, 20 mmol) in drydimethyl sulfoxide (30 mL) sodium hydride (60% dispersion in mineraloil) (0.720 g, 18 mmol) was added and the reaction mixture was stirredfor 1 hour at room temperature. A solution of ethyl2-[2,6-bis(methoxymethoxy)-3-methyl-phenyl]prop-2-enoate (Intermediate9, 3.5 g, 11.29 mmol) in dry dimethyl sulfoxide (15 mL) was slowly addedand the reaction mixture was stirred for 1 hour at room temperature. Thereaction was quenched with an aqueous saturated solution of ammoniumchloride (10 ml), diluted with water (40 ml) and extracted with ethylacetate (2×100 ml). The organic layer was washed with water (2×50 ml),dried over sodium sulphate, filtered and evaporated. The residue waspurified by flash chromatography (Biotage system) on silica gel using a100 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 8:2 aseluents affording the title compound (3.1 g) as a colourless oil.

LC/MS: QC_3_MIN: Rt=2.028 min.

Intermediate 112-[1-(hydroxymethyl)cyclopropyl]-3-(methoxymethoxy)-6-methyl-phenol

To a solution of ethyl1-[2,6-bis(methoxymethoxy)-3-methyl-phenyl]cyclopropanecarboxylate(Intermediate 10, 300 mg, 0.93 mmol) in ethanol (10 ml) HCl 6N in water(0.4 mL, 2.4 mmol) was added and the reaction mixture was stirredovernight at 50° C. Combined solvents were removed under reducedpressure. The residue was suspended in dry toluene (10 mL) and thesolvent evaporated. The obtained residue was dissolved in drytetrahydrofuran (10 ml), the mixture was cooled to 0° C. and NaH (60%dispersion in mineral oil) (80 mg, 2 mmol) was added and the reactionmixture was stirred for 30 minutes at the same temperature. MOM-Cl(0.083 mL, 1.1 mmol) was then added and the reaction mixture was stirredfor 1 hour at 0° C. LiAlH₄ (1M in THF, 1.2 ml, 1.2 mmol) was added andthe reaction mixture was further stirred for 1 hour at the sametemperature. The reaction was quenched with an aqueous saturatedsolution of ammonium chloride (10 ml), diluted with water (20 ml) andextracted with ethyl acetate (2×50 ml). Combined organic layers weredried over sodium sulphate, filtered and evaporated and the residue waspurified by flash chromatography (Biotage system) on silica gel using a25 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 7:3 aseluents affording the title compound (70 mg) as a white solid.

LC/MS: QC_3_MIN: Rt=1.690 min; 239 [M+H]+.

Intermediate 124-(methoxymethoxy)-7-methyl-spiro[2H-benzofuran-3,1′-cyclopropane]

To a solution of2-[1-(hydroxymethyl)cyclopropyl]-3-(methoxymethoxy)-6-methyl-phenol(Intermediate 11, 65 mg, 0.27 mmol) in dry tetrahydrofuran (5 ml)triphenylphosphine (84 mg, 0.32 mmol) was added and the reaction mixturewas stirred until complete dissolution of it. DIAD (0.056 ml, 0.285mmol) was then added dropwise and the reaction mixture was stirred for30 minutes at room temperature. The solvent was removed under reducedpressure and the residue was purified by flash chromatography (Biotagesystem) on silica gel using a 10 g SNAP column and cyclohexane tocyclohexane/ethyl acetate 8:2 as eluents affording the title compound(40 mg) as a light yellow oil.

LC/MS: QC_3_MIN: Rt=2.024 min; 221 [M+H]+.

Intermediate 13 7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-ol

To a solution of4-(methoxymethoxy)-7-methyl-spiro[2H-benzofuran-3,1′-cyclopropane](Intermediate 12, 38 mg, 0.17 mmol) in ethanol (5 ml), HCl 6N in water(0.1 mL, 0.6 mmol) was added and the reaction mixture was stirred for 4days at room temperature. Combined solvents were removed under reducedpressure and the residue was purified by flash chromatography (Biotagesystem) on silica gel using a 10 g SNAP column and cyclohexane tocyclohexane/ethyl acetate 7:3 as eluents affording the title compound(24 mg) as a light orange solid.

¹H-NMR (400 MHz, DMSO-d₆) δ ppm: 9.02 (1H, s), 6.65 (1H, d), 6.06 (1H,d), 4.36 (2H, s), 2.02 (3H, s), 1.40-1.44 (2H, m), 0.77-0.82 (2H, m).ROESY (400 MHz, DMSO-d₆): NOE correlation between proton at 6.65 ppm andprotons (CH3) at 2.02 ppm, NOE correlation between proton at 9.02 ppmand proton at 6.06 ppm. LC/MS: QC_3_MIN: Rt=1.647 min; 177 [M+H]+.

Intermediate 14

2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-5-nitro-pyridine

To a solution of 7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-ol(Intermediate 13, 176 mg, 1 mmol) in dry DMF (4 ml) potassium carbonate(207 mg, 1.5 mmol) and then 2-chloro-5-nitropyridine (158 mg, 1 mmol)were added and the reaction mixture was stirred for 2 hours at 80° C.After cooling the reaction mixture was quenched with water (2 ml),diluted with brine (10 ml) and extracted with ethyl acetate (2×20 ml).The organic layer was dried over sodium sulfate, filtered and evaporatedaffording the title compound (270 mg) as an orange solid that was usedin the next step as crude material without further purification.

LC/MS: QC_3_MIN: Rt=2.138 min; 299 [M+H]+.

Intermediate 156-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyridin-3-amine

To a solution of2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-5-nitro-pyridine(Intermediate 14, 265 mg) in tetrahydrofuran (5 ml)/water (2.5 ml) iron(245 mg, 4.45 mmol) and then ammonium chloride (238 mg, 4.45 mmol) wereadded and the reaction mixture was stirred overnight at roomtemperature. The catalyst was filtered off and the residue was dilutedwith an aqueous saturated solution of NaHCO₃ (5 ml) and extracted withethyl acetate (3×10 ml). The organic layer was dried over sodiumsulphate, filtered and evaporated and the residue was purified by flashchromatography (Biotage system) on silica gel using a 10 g SNAP columnand cyclohexane/ethyl acetate 8:2 to cyclohexane/ethyl acetate 1:1 aseluents affording the title compound (203 mg) as a light yellow solid.

LC/MS: QC_3_MIN: Rt=1.740 min; 269 [M+H]+.

Intermediate 16 tert-butylN-[(1R)-1-[[6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-3-pyridyl]carbamoyl]propyl]carbamate

To a solution of(2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (36 mg,0.18 mmol) in dry DMF (1 ml) DIPEA (52 μl, 0.3 mmol) and then HATU (65mg, 0.17 mmol) were added and the reaction mixture was stirred for 15minutes at r.t.6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyridin-3-amine(Intermediate 15, 40 mg, 0.15 mmol) was then added and the reactionmixture was stirred for 4 hours at room temperature. The reaction wasquenched with water (2 ml) diluted with brine (5 ml) and extracted withethyl acetate (2×10 ml). The organic layer was dried (Na₂SO₄), filteredand evaporated and the residue was purified by flash chromatography(Biotage system) on silica gel using a 10 g SNAP column andcyclohexane/ethyl acetate 90:10 to cyclohexane/ethyl acetate 60:40 aseluents affording the title compound (57 mg) as a white solid.

LC/MS: QC_3_MIN: Rt=2.190 min; 454 [M+H]+.

Intermediate 17(2R)-2-amino-N-[6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-3-pyridyl]butanamide

To a solution of tert-butylN-[(1R)-1-[[6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-3-pyridyl]carbamoyl]propyl]carbamate(Intermediate 16, 55 mg) in dry DCM (3 ml) at 0° C. TFA (1 ml) wasslowly added and the reaction mixture was stirred for 3 hours at thesame temperature. The solvent and the excess of TFA were removed underreduced pressure and the residue was diluted with DCM (10 ml) and anaqueous saturated solution NaHCO₃ was added while the pH was allowed toreach ^(˜)8. Two phases were separated and the organic layer was dried(Na₂SO₄), filtered and evaporated affording the title compound (41 mg)as white solid.

LC/MS: QC_3_MIN: Rt=1.792 min; 354 [M+H]+.

Intermediate 182-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-5-nitro-pyrimidine

To a solution of 7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-ol(Intermediate 13, 176 mg, 1 mmol) in dry Acetonitrile (4 ml) potassiumcarbonate (207 mg, 1.5 mmol) and then 2-chloro-5-nitropyrimidine (159mg, 1 mmol) were added and the reaction mixture was stirred for 24 hoursat 80° C. After cooling the reaction mixture was quenched with water (2ml), diluted with brine (10 ml) and extracted with ethyl acetate (2×20ml). The organic layer was dried over sodium sulfate, filtered andevaporated affording the title compound (258 mg) as an orange solid thatwas used in the next step as crude material without furtherpurification.

LC/MS: QC_3_MIN: Rt=2.007 min; 300 [M+H]+.

Intermediate 192-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-amine

To a solution of2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-5-nitro-pyrimidine(Intermediate 18, 255 mg) in tetrahydrofuran (5 ml)/water (2.5 ml) iron(234 mg, 4.25 mmol) and then ammonium chloride (227 mg, 4.25 mmol) wereadded and the reaction mixture was stirred for 48 hours at roomtemperature. The catalyst was filtered off and the residue was dilutedwith an aqueous saturated solution of NaHCO₃ (5 ml) and extracted withethyl acetate (3×10 ml). The organic layer was dried over sodiumsulphate, filtered and evaporated and the residue was purified by flashchromatography (Biotage system) on silica gel using a 10 g SNAP columnand cyclohexane/ethyl acetate 8:2 to cyclohexane/ethyl acetate 4:6 aseluents affording the title compound (52 mg) as a light orange solid.

LC/MS: QC_3_MIN: Rt=1.746 min; 270 [M+H]+.

Intermediate 20 ten-butylN-[(1R)-1-[[2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-yl]carbamoyl]propyl]carbamate

To a solution of(2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (45 mg,0.222 mmol) in dry DMF (1 ml) DIPEA (87 μl, 0.5 mmol) and then HATU (80mg, 0.21 mmol) were added and the reaction mixture was stirred for 15minutes at r.t.2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-amine(Intermediate 19, 50 mg, 0.185 mmol) was then added and the reactionmixture was stirred for 6 hours at room temperature. The reaction wasquenched with water (2 ml) diluted with brine (5 ml) and extracted withethyl acetate (2×10 ml). The organic layer was dried (Na₂SO₄), filteredand evaporated and the residue was purified by flash chromatography(Biotage system) on silica gel using a 10 g SNAP column andcyclohexane/ethyl acetate 90:10 to cyclohexane/ethyl acetate 60:40 aseluents affording the title compound (45 mg) as a white solid.

LC/MS: QC_3_MIN: Rt=2.109 min; 455 [M+H]+.

Intermediate 21(2R)-2-amino-N-[2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-yl]butanamide

To a solution of tert-butylN-[(1R)-1-[[2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-yl]carbamoyl]propyl]carbamate(Intermediate 20, 42 mg) in dry DCM (3 ml) at 0° C. TFA (1 ml) wasslowly added and the reaction mixture was stirred for 3 hours at thesame temperature. The solvent and the excess of TFA were removed underreduced pressure and the residue was diluted with DCM (10 ml) and anaqueous saturated solution NaHCO₃ was added while the pH was allowed toreach ^(˜)8. Two phases were separated and the organic layer was dried(Na₂SO₄), filtered and evaporated affording the title compound (25 mg)as light yellow gum.

LC/MS: QC_3_MIN: Rt=1.688 min; 355 [M+H]+.

Intermediate 22(5R)-3-(2-chloropyrimidin-5-yl)-5-ethyl-5-methyl-imidazolidine-2,4-dione

To a solution of triphosgene (1.38 g, 4.65 mmol) in Ethyl acetate (20ml) at 0° C. a solution of 2-chloro-5-aminopyrimidine (1 g, 7.75mmol)/DIPEA (8 ml, 4.65 mmol) in ethyl acetate (40 ml) was slowly added(20 minutes) and the reaction mixture was stirred for 15 minutes at thesame temperature. Maintaining the reaction mixture at 0° C., vacuum wasapplied (10 minutes) for removing the excess of phosgene. A solution ofDMAP (0.945 g, 7.75 mmol) in ethyl acetate/dichloromethane 1:1 (8 ml)was added and the reaction mixture was stirred for 5 minutes at the sametemperature. A solution of methyl (R)-2-amino-2-methyl-butyratehydrochloride (2.59 g, 15.5 mmol) in ethyl acetate (30 ml) was slowlyadded (15 minutes) at 0° C. and the reaction mixture was stirred for 30minutes at the same temperature. The reaction was quenched with aqueousbuffer (pH3) while the pH was allowed to reach ^(˜)5-6 and two phaseswere separated. The organic layer was washed with aqueous buffer (pH3)(2×20 ml) and then brine (20 ml), dried (Na₂SO₄), filtered andevaporated affording the urea intermediate as orange foam.

The urea was dissolved in MeOH (20 ml), NaOMe (0.41 g, 7.75 mmol) wasadded and the reaction mixture was stirred for 15 minutes at r.t. Themixture was quenched with an aqueous saturated solution of ammoniumchloride (25 ml) and diluted with ethyl acetate (50 ml). Two phases wereseparated and the organic layer was washed with brine (2×20 ml), dried(Na₂SO₄), filtered and evaporated. The residue was triturated with Et₂O(10 ml) and the solid collected affording the title compound (1.22 g) asa beige solid.

LC/MS: QC_3_MIN: Rt=1.341 min; 255 [M+H]+.

Intermediate 233-(2-chloropyrimidin-5-yl)-5,5-dimethyl-imidazolidine-2,4-dione

To a solution of triphosgene (1.38 g, 4.65 mmol) in Ethyl acetate (20ml) at 0° C. a solution of 2-chloro-5-aminopyrimidine (1 g, 7.75mmol)/DIPEA (8 ml, 4.65 mmol) in ethyl acetate (40 ml) was slowly added(20 minutes) and the reaction mixture was stirred for 15 minutes at thesame temperature. Maintaining the reaction mixture at 0° C., vacuum wasapplied (10 minutes) for removing the excess of phosgene. A solution ofDMAP (0.945 g, 7.75 mmol) in ethyl acetate/dichloromethane 1:1 (8 ml)was added and the reaction mixture was stirred for 5 minutes at the sametemperature. 2,2-Dimethylglycine methyl ester hydrochloride (2.37 g,15.5 mmol) in ethyl acetate (30 ml) was slowly added (15 minutes) at 0°C. and the reaction mixture was stirred for 30 minutes at the sametemperature. The reaction was quenched with aqueous buffer (pH3) whilethe pH was allowed to reach ^(˜)5-6 and two phases were separated. Theorganic layer was washed with aqueous buffer (pH3) (2×20 ml) and thenbrine (20 ml), dried (Na₂SO₄), filtered and evaporated affording theurea intermediate as orange foam.

The urea was dissolved in MeOH (20 ml), NaOMe (0.41 g, 7.75 mmol) wasadded and the reaction mixture was stirred for 15 minutes at r.t. Themixture was quenched with an aqueous saturated solution of ammoniumchloride (25 ml) and diluted with ethyl acetate (50 ml). Two phases wereseparated and the organic layer was washed with brine (2×20 ml), dried(Na₂SO₄), filtered and evaporated. The residue was triturated with Et₂O(10 ml) and the solid collected affording the title compound (1.08 g) asan orange solid.

LC/MS: QC_3_MIN: Rt=1.062 min; 241 [M+H]+.

Intermediate 24[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy][tris(1-methylethyl)]silane

3,3-Dimethyl-2,3-dihydro-1-benzofuran-4-ol (Intermediate 6, 3.6 g, 21.91mmol) was dissolved in anhydrous THF (20.0 mL) and the colorlesssolution was cooled to 0° C. stirring under nitrogen. A 2M n-BuLisolution in cyclohexane (13.2 mL, 26.4 mmol) was added drop wise and theresulting yellow solution was stirred at 0° C. for 10 min.Triisopropylsislyltriflate (7.7 mL, 28.5 mmol) was added drop wise: thesolution discolored almost completely. This was allowed to warm to roomtemperature and stirred over night. Water (1.0 mL) was added to andvolatiles evaporated under reduced pressure. The residue was dissolvedin ethyl acetate and washed with brine three times. The organic layerwas dried over anhydrous Na₂SO₄ and evaporated to dryness to give yellowoil which was re-dissolved in TBME and washed twice with water. Theorganic solution was dried over Na₂SO₄ and evaporated to dryness to givethe title compound (7.4 g) as a yellow oil.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.94 (1H, t), 6.31-6.36 (1H, m), 6.29(1H, d), 4.14 (2H, s), 1.28-1.40 (9H, m), 1.09 (18H, d).

Intermediate 25[(7-bromo-3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy][tris(1-methylethyl)]silane

[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy][tris(1-methylethyl)]silane(Intermediate 24, 7.4 g, 23.19 mmol) was dissolved in THF (70.0 mL).N-Bromosuccinimide (4.2 g, 23.88 mmol) was added dissolving in fewminutes. This mixture was stirred at room temperature for 3 hrs. MoreNBS (0.64 g, 3.48 mmol) was added and the reaction mixture was stirredat room temperature for a further hour. CCl₄(50 mL) was added to thereaction mixture and the solution was evaporated to dryness. The residuewas re-suspended in CCl₄ and stirred at room temperature for 15 min. Thewhite solid was removed by filtration and the wet cake was washed withmore CCl₄. The CCl₄ was swapped with ethyl acetate and the organicsolution was washed three times with 2.5% w/w aqueous NaHCO₃ and finallywith water. The organic solution was dried on anhydrous Na₂SO₄ andevaporated to dryness to give the title compound (8.6 g) as a brown oil.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.14 (1H, d), 6.29 (1H, d), 4.24 (2H,s), 1.27-1.41 (9H, m), 1.08 (18H, d).

Intermediate 26tris(1-methylethyl)[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]silane

[(7-bromo-3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy][tris(1-methylethyl)]silane(Intermediate 25, 7.1 g, 17.72 mmol) was dissolved in anhydrous THF (72mL) and cooled to 0° C. Tetramethylethylenediamine (8.0 mL, 53.16 mmol)was added and the yellow solution was stirred at 0° C. for 10 min. Asolution of 1.6 M butyllithium in hexane (22.5 mL, 35.4 mmol) was addeddrop wise over 10 minutes and then stirred at 0° C. for 15 min. Methyliodide (11 mL, 177.2 mmol) was added drop wise over 6 min. The whitesolid was removed by filtration and the wet cake was washed in with THF.The combined organic layers were evaporated to dryness. The residue wasdissolved in ethyl acetate and washed twice with aqueous NaHCO₃ and oncewith water. The organic solution was dried on anhydrous Na₂SO₄ andevaporated to dryness. to give brown oil. The residue was purified byflash chromatography on silica gel using cyclohexane tocyclohexane/ethyl acetate 1:1 as eluents affording the title compound(3.6 g) as a brown oil.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.76 (1H, d), 6.20 (1H, d), 4.14 (2H,s), 2.02 (3H, s), 1.28-1.39 (9H, m), 1.09 (18H, d).

Intermediate 27 3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-ol

Tris(1-methylethyl)[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]silane(Intermediate 26, 3.6 g, 10.84 mmol) was dissolved in THF (36 mL) toobtain a dark yellow solution. TBAF (8.5 g, 32.5 mmol) was added and thereaction mixture was stirred overnight at room temperature. The solventwas removed under reduced pressure. The residue was dissolved in ethylacetate and washed with aqueous HCl, then aqueous NaHCO₃ and finallybrine. The organic solution was dried over Na₂SO₄ and evaporated todryness and the residue was purified by flash chromatography on silicagel using cyclohexane to cyclohexane/ethyl acetate 95:5 as eluentsaffording the title compound (1.69 g) as colorless oil.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.06 (1H, s), 6.65-6.69 (1H, m), 6.19(1H, d), 4.11 (2H, s), 1.99 (3H, s), 1.33 (6H, s).

Intermediate 285-nitro-2[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]pyridine

3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-ol (Intermediate 27, 0.9 g,5.0 mmol) was dissolved in CH₃CN (5 mL) in the presence of2-chloro-5-nitropyridine (790 mg, 5.0 mmol) and K₂CO₃ (1.72 g, 12.5mmol) and the resulting suspension was heated to 60° C. for 1.5 hrs. Themixture was then cooled to room temperature and diluted with water andethyl acetate. Two phases were separated and the organic layer waswashed with brine, then dried over Na₂SO₄ and evaporated to dryness, Theresidue was purified by flash chromatography on silica gel usingcyclohexaneto cyclohexane/ethyl acetate 90:10 as eluents affording thetitle compound (0.92 g) as yellowish solid.

¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.04 (1H, d), 8.61 (1H, dd), 7.24 (1H,d), 7.02 (1H, d), 6.54 (1H, d), 4.21 (2H, s), 2.14 (3H, s), 1.21 (6H,s). ¹³C-NMR (200 MHz, DMSO-d₆): δ ppm 166.6, 158.7, 147.2, 144.8, 140.4,135.8, 130.2, 126.1, 116.7, 114.5, 111.0, 83.6, 42.2, 26.0, 14.4.

Intermediate 296-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinamine

5-Nitro-2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]pyridine(Intermediate 28, 920 mg, 3.0 mmol) was dissolved in EtOH (13.5 mL) andstirred under hydrogen atmosphere (2 bar) in the presence of Pd/C 10%w/w (46 mg, 5% w/w) at room temperature for 30 minutes. The catalyst wasfiltered off, washed with THF and the resulting solution evaporated todryness to afford an orange solid. The crude product was crystallizedfrom MeOH to the title compound (565 mg) as a beige solid.

¹H-NMR (400 MHz, DMSO-d₆): δ ppm 7.51 (1H, d), 7.05 (1H, dd), 6.85 (1H,d), 6.69 (1H, d), 6.21 (1H, d), 5.04 (2H, br.s), 4.19 (2H, s), 2.08 (3H,s), 1.30 (6H, s). ¹³C-NMR (200 MHz, DMSO-d₆): δ ppm 158.3, 154.2, 150.7,141.5, 132.2, 129.6, 125.3, 124.7, 113.9, 112.2, 111.8, 83.7, 42.2,26.0, 14.4.

Intermediate 30 1,1-dimethylethyl{(1R)-1[({6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}amino)carbonyl]propyl}carbamate

6-{[3,3,7-Trimethyl-6-(trifluoromethoxy)-2,3-dihydro-1-benzofuran-4-yl]oxy}pyridin-3-amine(Intermediate 29, 405 mg, 1.27 mmol) was suspended in ethyl acetate (4mL). Triethylamine (0.44 ml, 3.175 mmol) was added followed by theaddition of (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoicacid (258 mg, 1.27 mmol). The resulting suspension was cooled to 0° C.and T3P 50% w/w solution in ethyl acetate (1.4 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 hour and thenwarmed to room temperature and stirred for a further hour. An aqueoussaturated solution of Na₂CO₃ was added and the mixture stirred for 10min. Two phases were separated and the organic layer was washed withwater and brine, dried over Na₂SO₄ and evaporated to dryness. Theresidue was purified by flash chromatography on silica gel usingcyclohexane/ethyl acetate 80:20 to cyclohexane/ethyl acetate 70:30 aseluents affording the title compound (0.50 g) as white foam.

¹H-NMR (400 MHz, DMSO-d₆): δ ppm 10.08 and 10.03 (1H, br.s), 8.30 (1H,d), 8.03 (1H, dd), 7.00 (1H, d), 6.95-6.90 (2H, m), 6.36 (1H, d), 4.17(2H, s), 3.98-3.92 (1H, m), 2.10 (3H, s), 1.73-1.52 (2H, m), 1.36 and1.29 (9H, br.s), 1.23 (6H, s), 0.88 (3H, t). ¹³C-NMR (200 MHz, DMSO-d₆):δ ppm 171.4, 159.0, 158.5, 155.5, 148.9, 138.1, 131.4, 129.8, 125.8,115.1, 113.9, 110.7, 83.6, 78.0, 56.3, 42.2, 28.9, 26.0, 25.0, 20.7,14.4, 14.1, 10.5.

Intermediate 31(2R)-2-amino-N-{6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}butanamide

The 1,1-dimethylethyl{(1R)-1-[({6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}amino)carbonyl]propyl}carbamate(Intermediate 30, 480 mg, 1.05 mmol) was dissolved in iso-propyl acetate(5 mL) and HCl 5-6N in isopropanol (1 ml, 5.25 mmol) was added. Thesolution was stirred at room temperature for 1 hour and then heated to^(˜)50-55° C. until complete conversion. The mixture was cooled to roomtemperature and treated with an aqueous saturated solution of NaHCO₃.Two phases were separated and the organic layer was washed with brine,dried over Na₂SO₄ and evaporated to dryness. The residue was purified byflash chromatography on silica gel using dichloromethane/methanol 95:5as eluents affording the title compound (0.31 g) as yellowish foam.

¹H-NMR (400 MHz, DMSO-d₆): δ ppm 8.36 (1H, d), 8.11 (1H, dd), 6.96-6.92(2H, m), 6.38 (1H, d), 4.19 (2H, s), 3.23 (1H, dd), 2.11 (3H, s),1.72-1.61 (1H, m), 1.53-1.43 (1H, m), 1.25 (6H, s), 0.90 (3H, t).¹³C-NMR (200 MHz, DMSO-d₆): δ ppm 174.5, 159.0, 158.5, 148.9, 138.2,131.5, 131.4, 129.8, 125.7, 115.1, 113.9, 110.6, 83.6, 56.7, 42.2, 28.0,26.0, 14.4, 10.2.

Intermediate 325-nitro-2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]pyrimidine

3,3,7-Trimethyl-2,3-dihydro-1-benzofuran-4-ol (Intermediate 27, 178 mg,1.0 mmol) and 2-chloro-5-nitropyrimidine (191.5 mg, 1.2 mmol) weredissolved in CH₃CN (3.0 mL) and K₂CO₃ (345.5 mg, 2.5 mmol) was added.The resulting suspension was heated to 40° C. and stirred for 1 hour.The reaction mixture was then diluted with water (50 mL) and ethylacetate (50 mL), The organic phase was collected, washed with brine (50mL) and dried over Na₂SO₄. The residue was purified by flashchromatography on silica gel using cyclohexane/ethyl acetate 97:3 aseluents affording the title compound (243 mg).

Intermediate 332-[(3,3,7-trimethyl-23-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinamine

5-nitro-2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]pyrimidine(Intermediate 32, 243 mg, 0.81 mmol) was dissolved in THF (4 mL) andPalladium on charcoal (5 mol %, 85 mg) was added. The reaction mixturewas stirred under hydrogen atmospèhere (3 bar) for 1 hour at roomtemperature. The catalyst was filtered on a pad of celite, washed withTHF and the resulting solution was concentrated under vacuum. Theresidue was diluted with ethyl acetate and water, the organic phasecollected, dried over Na₂SO₄ and evaporated to afford the title compound(220 mg) as colorless oil. The crude product, was used in the next stepwithout further purification.

MS_2 (ESI): 272 [M+H]+

Intermediate 34 1,1-dimethylethyl{(1R)-1-[({2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}amino)carbonyl]propyl}carbamate

2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinamine(Intermediate 33, 220 mg, 0.81 mmol) was dissolved in ethyl acetate (10mL) and of (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid(181.1 mg, 0.89 mmol) was added followed by the addition of Et₃N (0.35mL, 2.02 mmol). The resulting solution was cooled down to 5° C. and asolution of T3P 50% w/w in ethyl acetate (0.53 mL, 0.89 mmol) was addeddrop wise in 15 min. The reaction mixture was stirred for 30 min at 5°C. The reaction was quenched with water (50 mL) and ethyl acetate (50mL), two phases were separated and the organic layer was dried overNa₂SO₄ and concentrated under vacuum. The residue was purified by flashchromatography on silica gel using cyclohexane/ethyl acetate 60:40 aseluent affording the title compound (213 mg).

MS_2 (ESI):457 [M+H]+.

Intermediate 35 (2,2-difluoro-1,3-benzodioxol-4-yl)boronic acid

2,2-Difluoro-1,3-benzodioxole (960 mg, 6.1 mmol) was dissolved in THF (8mL) and cyclohexane (4 mL) and the resulting solution cooled to −78° C.sec-BuLi 1.4M solution in cyclohexane (4.3 mL, 6.1 mmol) was addeddropwise and the reaction mixture stirred for 1.5 hours at −78° C.Trimethylborate (694 mg, 6.75 mmol) was added and the mixture wasallowed to warm slowly to −30° C. The reaction mixture was quenched witha 2N solution of HCl and diluted with ethyl acetate. Two phases wereseparated and the organic layer was washed twice with brine, dried overNa₂SO₄ and evaporated to dryness affording the title compound as yellowoil which was used in the next step without further purification.

¹H-NMR (400 MHz, DMSO-d₆+D₂O): 6 ppm 7.39 (1H, dd), 7.34 (1H, dd), 7.14(t, 1H, J=7.90 Hz). ¹⁹F-NMR (376 MHz, DMSO-d₆+D₂O): 6 ppm −48.92.¹³C-NMR (200 MHz, DMSO-d₆+D₂O): δ ppm 147.3, 142.8, 131.6 (t, J=250.7Hz), 130.1, 124.3, 112.0

Intermediate 36 (2,2-difluoro-7-methyl-1,3-benzodioxol-4-yl)boronic acid

(2,2-difluoro-1,3-benzodioxol-4-yl)boronic acid (Intermediate 35, crudematerial) was dissolved in THF (20 mL) and the resulting solution cooleddown to −78° C. sec-BuLi 1.4M solution in cyclohexane (17.4 ml, 24.36mmol) was added dropwise and the reaction mixture was stirred for 1.5hours at −78° C. Methyl iodide (4.6 ml, 73 mmol) was then added and thereaction mixture was stirred for 2 hours while the temperature wasallowed to reach room temperature. The reaction was quenched by additionof an aqueous 2N solution of HCl and diluted with ethyl acetate. Theorganic layer was collected and then washed twice with brine, dried overNa₂SO₄ and evaporated to dryness. Crystallization from n-heptaneafforded the title compound (150 mg) as white solid.

¹H-NMR (400 MHz, DMSO-d₆+D₂O): δ ppm 7.30 (1H, d), 6.68 (1H, d), 2.25(s, 3H). ¹⁹F-NMR (376 MHz, DMSO-d₆+D₂O): δ ppm −48.55. ¹³C-NMR (200 MHz,DMSO-d₆+D₂O): δ ppm 152.5, 147.1, 141.5, 131.6 (t, J=250.0 Hz), 129.9,125.8, 122.7, 110.1, 14.6.

Intermediate 37 2,2-difluoro-7-methyl-1,3-benzodioxol-4-ol

(2,2-difluoro-7-methyl-1,3-benzodioxol-4-yl)boronic acid (Intermediate36, 150 mg, 1.28 mmol) was dissolved in THF (1.5 mL) and a 30% w/waqueous solution of H₂O₂ (2.56 mmol) and NaOH (51 mg, 1.28 mmol) wereadded and the reaction mixture stirred for 2 days at room temperature.The reaction was quenched with a 2N aqueous solution of HCl and dilutedwith ethyl acetate. Two phases were separated and the organic layer waswashed twice with brine, dried over Na₂SO₄ and evaporated to dryness,affording the title compound (140 mg) as yellow oil.

¹H-NMR (400 MHz, DMSO-d₆): δ ppm 10.31 (1H, s), 6.83 (1H, d), 6.63 (1H,d), 2.17 (3H, s). ¹⁹F-NMR (376 MHz, DMSO-d₆): δ ppm −48.68. ¹³C-NMR (200MHz, DMSO-d₆): δ ppm 142.3, 139.1, 131.4 (t, J=251.9 Hz), 129.9, 125.6,112.8, 110.0, 13.2.

Intermediate 38 2-bromo-3-hydroxyphenyl acetate

To a solution of 2-bromo-1,3-benzenediol (3.028 g, 16.02 mmol) indichloromethane (70 ml), TEA (3.35 ml, 24.03 mmol) and acetic anhydride(1.512 ml, 16.02 mmol) were added under stirring. The reaction mixturewas stirred at room temperature overnight. The reaction was quenchedwith a saturated solution of ammonium chloride (100 ml), and extractedwith ethyl acetate (3 times 70 ml). The combined organic layers weredried over sodium sulphate, filtered and evaporated to afford the titlecompound as a black oil which was used directly used in the next step.(3.028 g)

UPLC_B: 0.41 min, 229 [M−H]−

Intermediate 39 2-bromo-3-[(2-methyl-2-propen-1-yl)oxy]phenyl acetate

To a solution of 2-bromo-3-hydroxyphenyl acetate (Intermediate 38, 3028mg) in acetonitrile (60 ml) potassium carbonate (3623 mg, 26.2 mmol) and3-bromo-2-methyl-1-propene (2123 mg, 15.73 mmol) were added. Thereaction mixture was stirred at room temperature overnight. The mixturewas washed with water (3 times 60 ml). The organic phase was separated,dried over sodium sulphate, filtered and evaporated. The residue waspurified by flash chromatography on silica gel using a 100 g-SNAP columnand cyclohexane/ethyl acetate from 100/0 to 80/20 as eluent to affordthe title compound as a colourless oil (2.324 g).

¹H NMR (400 MHz, CDCl₃): δ ppm 7.27 (1H, t), 6.68 (1H, dd), 5.19 (1H,s), 5.04 (1H, s), 4.53 (2H, s), 2.38 (3H, s), 1.88 (3H, s); UPLC: 0.81min, 285 [M+H]+

Intermediate 40 3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl acetate

To a solution of 2-bromo-3-[(2-methyl-2-propen-1-yl)oxy]phenyl acetate(Intermediate 39, 2.324 g) in toluene (20 ml) AIBN (1.606 g, 9.78 mmol)and tributylstannane (4.73 g, 16.30 mmol) were added. The reactionmixture was stirred and heated at 100° C. for 2 hours, then was left atroom temperature for 4 hours. The reaction was quenched with water (60ml) and extracted with ethyl acetate (3 times 50 ml). The combinedorganic layers were dried over sodium sulphate, filtered and evaporated.The residue was purified by flash chromatography on silica gel using a100 g-SNAP column and cyclohexane/ethyl acetate from 100/0 to 70/30 aseluent to afford the title compound as a colourless oil (1.290 g).

¹H NMR (400 MHz, CDCl₃): δ ppm 7.13 (1H, t), 6.68 (1H, d), 6.59 (1H, d),4.22 (2H, s), 2.33 (3H, s), 1.39 (6H, s). UPLC: 0.72 min, 207 [M+H]+

Intermediate 6 3,3-dimethyl-2,3-dihydro-1-benzofuran-4-ol

This is an alternative synthetic route to the one described previouslyfor Intermediate 6.

To a solution of 3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl acetate(Intermediate 40, 1.290 g) in methanol (50 ml) a solution of sodiumhydroxide (0.375 g, 9.38 mmol) in water (25.00 ml) was added. Thereaction mixture was stirred at room temperature for 30 minutes. Themixture was then acidified with HCl 5% until pH=5 and extracted withethyl acetate (3 times 50 ml). The combined organic layers were driedover sodium sulphate, filtered and evaporated. The residue was purifiedby flash chromatography on silica gel using a 25 g-SNAP column andcyclohexane/ethyl acetate from 100/0 to 80/20 as eluent to afford thetitle compound as a white solid (855 mg).

UPLC: 0.65 min, 165 [M+H]+

Example 1(5R)-5-ethyl-5-methyl-3-[2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2,4-dione

To a solution of 7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-ol(Intermediate 13, 18 mg, 0.1 mmol) in dry DMF (1 ml) potassium carbonate(27.6 mg, 0.2 mmol) and then(5R)-3-(2-chloropyrimidin-5-yl)-5-ethyl-5-methyl-imidazolidine-2,4-dione(Intermediate 22, 20 mg, 0.08 mmol) were added and the reaction mixturewas stirred for 2 hours at 80° C. After cooling the reaction mixture wasquenched with water (1 ml), diluted with brine (5 ml) and extracted withethyl acetate (2×10 ml). The organic layer was dried over sodiumsulfate, filtered and evaporated and the residue was purified by flashchromatography (Biotage system) on silica gel using a 10 g SNAP columnand cyclohexane/ethyl acetate 7:3 to cyclohexane/ethyl acetate 3:7 aseluents affording the title compound (21 mg) as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ ppm: 8.69-8.74 (3H, m), 6.94 (1H, d), 6.52(1H, d), 4.44 (2H, s), 2.15 (3H, s), 1.73-1.83 (1H, m), 1.63-1.73 (1H,m), 1.40 (3H, s), 1.02-1.06 (2H, m), 0.85-0.92 (5H, m). LC/MS: QC_3_MIN:Rt=2.007 min; 395 [M+H]+.

The following compounds were prepared using the foregoing methodology,replacing 7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-ol(Intermediate 13) with the appropriate phenol. Final products werepurified by flash-chromatography (Silica cartridge; Cyclohexane/EtOAc orother appropriate solvent system).

Ex. Structure Name Phenol ¹H-NMR LCMS 2

(5R)-5-ethyl-5- methyl-3-{2- [(3,3,7-trimethyl- 2,3-dihydro-1-benzofuran-4- yl)oxy]-5- pyrimidinyl}-2,4- imidazolidinedione 3,3,7-trimethyl- 2,3- dihydro-1- benzofuran- 4-ol (Intermediate 27) ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 8.70 (1H, br.s), 8.69 (2H, s), 6.98 (1H, d),6.55 (1H, d), 4.19 (2H, s), 2.12 (3H, s), 1.90-1.50 (1H, m), 1.38 (3H,s), 1.21 (6H, s), 0.86 (3H, t). UPLC: 1.06 min, 397 [M + H]+ 3

(5R)-3-{2-[(2,2- difluoro-7- methyl-1,3- benzodioxol-4- yl)oxy]-5-pyrimidinyl}-5- ethyl-5-methyl- 2,4- imidazolidinedione 2,2- difluoro-7-methyl-1,3- benzodioxol- 4-ol (Intermediate 37) ¹H-NMR (400 MHz,DMSO-d₆): δ ppm 8.78 (2H, s), 8.74 (1H, br.s), 7.18-7.13 (2H, m), 2.33(3H, s), 1.84-1.75 (1H, m), 1.71-1.62 (1H, m), 1.40 (3H, s), 0.88 (3H,t. UPLC: 1.11 min, 407 [M + H]+,

Example 45,5-dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2,4-dione

To a solution of 7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-ol(Intermediate 13, 18 mg, 0.1 mmol) in dry DMF (1 ml) potassium carbonate(27.6 mg, 0.2 mmol) and then3-(2-chloropyrimidin-5-yl)-5,5-dimethyl-imidazolidine-2,4-dione(Intermediate 23, 20 mg, 0.083 mmol) were added and the reaction mixturewas stirred for 2 hours at 80° C. After cooling the reaction mixture wasquenched with water (1 ml), diluted with brine (5 ml) and extracted withethyl acetate (2×10 ml). The organic layer was dried over sodiumsulfate, filtered and evaporated and the residue was purified by flashchromatography (Biotage system) on silica gel using a 10 g SNAP columnand cyclohexane/ethyl acetate 7:3 to cyclohexane/ethyl acetate 3:7 aseluents affording the title compound (18 mg) as a light beige solid.

¹H-NMR (400 MHz, DMSO-d₆) δ ppm: 8.74 (1H, s), 8.70 (2H, s), 6.94 (1H,d), 6.52 (1H, d), 4.44 (2H, s), 2.14 (3H, s), 1.42 (6H, s), 1.01-1.06(2H, m), 0.87-0.92 (2H, m). LC/MS: QC_3_MIN: Rt=1.946 min; 380 [M+H]+.

Example 5(5R)-5-ethyl-3-[2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2,4-dione

To a solution of(2R)-2-amino-N-[2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-yl]butanamide(Intermediate 21, 24 mg, 0.068 mmol) in dry DCM (3 ml) TEA (0.028 ml,0.2 mmol) was added and the reaction mixture was cooled to 0° C. Asolution of triphosgene (15 mg, 0.05 mmol) in dry

DCM (1.5 ml) was slowly added and the reaction mixture was stirred for15 minutes at the same temperature. The reaction was quenched with water(10 ml) and two phases were separated. The organic layer was dried(Na₂SO₄), filtered and evaporated and the residue was purified purifiedby flash chromatography (Biotage system) on silica gel using a 10 g SNAPcolumn and cyclohexane/ethyl acetate 75:25 to cyclohexane/ethyl acetate25:75 as eluents affording the title compound (11 mg) as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ ppm: 8.75 (1H, s), 8.68 (2H, s), 6.94 (1H,d), 6.52 (1H, d), 4.44 (2H, s), 4.20-4.25 (1H, m), 2.15 (3H, s),1.77-1.88 (1H, m), 1.66-1.76 (1H, m), 1.02-1.06 (2H, m), 0.96 (3H, t),0.87-0.92 (2H, m). LC/MS: QC_3_MIN: Rt=1.955 min; 381 [M+H]+.

Example 6(5R)-5-ethyl-3-[6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-2,4-dione

To a solution of(2R)-2-amino-N-[6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-3-pyridyl]butanamide(Intermediate 17, 40 mg, 0.11 mmol) in dry DCM (5 ml) TEA (0.042 ml, 0.3mmol) was added and the reaction mixture was cooled to 0° C. A solutionof triphosgene (23.7 mg, 0.08 mmol) in dry DCM (3 ml) was slowly addedand the reaction mixture was stirred for 15 minutes at the sametemperature. The reaction was quenched with water (10 ml) and two phaseswere separated. The organic layer was dried (Na₂SO₄), filtered andevaporated and the residue was purified purified by flash chromatography(Biotage system) on silica gel using a 10 g SNAP column andcyclohexane/ethyl acetate 75:25 to cyclohexane/ethyl acetate 25:75 aseluents affording the title compound (22 mg) as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ ppm: 8.63 (1H, s), 8.13 (1H, d), 7.84 (1H,dd), 7.07 (1H, d), 6.94 (1H, d), 6.44 (1H, d), 4.46 (2H, s), 4.19-4.24(1H, m), 2.15 (3H, s), 1.77-1.88 (1H, m), 1.65-1.75 (1H, m), 1.10-1.14(2H, m), 0.96 (3H, t), 0.87-0.92 (2H, m). LC/MS: QC_3_MIN: Rt=2.025 min;380 [M+H]+.

Example 7(5R)-5-ethyl-3-{6-[(3,3,7-trimethyl-23-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione

(2R)-2-amino-N-{6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}butanamide(Intermediate 31, 300 mg, 0.84 mmol) was dissolved in ethyl acetate (6mL). Triethylamine (0.47 ml, 3.36 mmol) was added and the reactionmixture was cooled to 0° C. A solution of triphosgene (100 mg, 0.34mmol) in ethyl acetate (6 mL) was slowly added. At the end of additionthe mixture was treated with an aqueous saturated solution of NaHCO₃ andtwo phases were separated. The organic layer was washed with brine,dried over Na₂SO₄ and evaporated to dryness to obtain a waxy solid. Theresidue was purified purified by flash chromatography on silica gelusing cyclohexane/ethyl acetate 70:30 to cyclohexane/ethyl acetate 50:50as eluents affording the title compound (166 mg) as a white foam.

¹H-NMR (400 MHz, DMSO-d₆): δ ppm 8.61 (1H, br.s), 8.12 (1H, d), 7.82(1H, dd), 7.10 (1H, d), 6.98 (1H, d), 6.47 (1H, d), 4.21 (2H, s), 4.18(1H, br.s), 2.13 (3H, s), 1.86-176 (1H, m), 1.75-1.64 (1H, m), 1.25 (6H,s), 0.95 (3H, t). ¹³C-NMR (200 MHz, DMSO-d₆): δ ppm 173.2, 162.5, 158.6,155.4, 148.2, 145.2, 138.5, 130.0, 126.1, 124.3, 115.7, 114.4, 110.6,83.6, 57.5, 42.2, 26.0, 24.4, 14.4, 8.8.

Example 8(5R)-5-ethyl-3-{2-[(3,3,7-trimethyl-23-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}-2,4-imidazolidinedione

1,1-dimethylethyl{(1R)-1-[({2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}amino)carbonyl]propyl}carbamate(Intermediate 34, 213 mg, 0.47 mmol) was dissolved in HCl 5-6 N inisopropanol (1 mL) and the resulting solution was heated to 35° C. for30 minutes. The reaction mixture was then concentrated under vacuum, theresidue diluted with ethyl acetate (50 mL) and an aqueous 5% solution ofK₂CO₃ (30 mL). Two phases were separated and the organic layer waswashed with an aqueous saturated solution of ammonium chloride (30 mL),dried over Na₂SO₄ and concentrated under vacuum. The resulting crude wasdissolved in ethyl acetate (10 mL) and triethylamine was added (0.23 mL,1.64 mmol). The reaction mixture was cooled to 0-5° C. and a solution oftriphosgene (55 mg, 0.185 mmol) in ethyl acetate (5 mL) was added dropwise in 10 minutes. The reaction was quenched with water (50 mL) andextracted with ethyl acetate (50 mL). The organic layer was washed withbrine dried over Na₂SO₄ and concentrated under vacuum. The residue waspurified purified by flash chromatography on silica gel usingcyclohexane/ethyl acetate 50:50 as eluent affording the title compound(161 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d₆): δ ppm 8.72 (1H, s), 8.66 (2H, s), 7.03-6.93(1H, m), 6.55 (1H, d), 4.18 (2H, s), 2.12 (3H, s), 1.87-1.61 (2H, m),1.2 (6H, s), 1.15 (1H, t), 0.94 (3H, t). MS_2 (ESI): 383 [M+H].

Example 9(5R)-5-ethyl-5-methyl-3-[6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-2,4-dione

To a solution of triphosgene (30 mg, 0.1 mmol) in dry DCM (1 ml) at 0°C., under nitrogen atmosphere, DIPEA (0.175 ml, 1.0 mmol) was addedfollowed by the addition (slowly added) of a solution of6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyridin-3-amine(Intermediate 15, 27 mg, 0.1 mmol) in dry DCM (2 ml) and the reactionmixture was stirred for 15 minutes at the same temperature. After that asolution of Methyl (R)-2-amino-2-methyl-butyrate hydrochloride (33 mg,0.2 mmol) in dry DCM (2 ml) was added and the reaction mixture wasstirred for 30 minutes at 0° C. The reaction was quenched with a 1Maqueous solution of HCl (5 ml), diluted with DCM (10 ml) and two phaseswere separated. The organic layer was washed with brine (10 ml), dried(Na₂SO₄), filtered and evaporated affording the urea intermediate asyellow foam.

The urea was dissolved in MeOH (5 ml), NaOMe (10 mg) was added and thereaction mixture was stirred for 15 minutes at room temperature. Thereaction was quenched with an aqueous saturated solution of ammoniumchloride (20 ml) and diluted with ethyl acetate (40 ml). Two phases wereseparated and the organic layer was dried (Na₂SO₄), filtered andevaporated and the residue was purified by flash chromatography (Biotagesystem) on silica gel using a 10 g SNAP column and cyclohexane/ethylacetate 75:25 to cyclohexane/ethyl acetate 25:75 as eluents affordingthe title compound (29 mg) as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ ppm: 8.60 (1H, s), 8.15 (1H, d), 7.85 (1H,dd), 7.06 (1H, d), 6.94 (1H, d), 6.44 (1H, d), 4.46 (2H, s), 2.15 (3H,s), 1.73-1.83 (1H, m), 1.62-1.72 (1H, m), 1.40 (3H, s), 1.10-1.14 (2H,m), 0.84-0.92 (5H, m). LC/MS: QC_3_MIN: Rt=2.076 min; 394 [M+H]+.

Example 105,5-dimethyl-3-[6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-2,4-dione

To a solution of triphosgene (30 mg, 0.1 mmol) in dry DCM (1 ml) at 0°C., under nitrogen atmosphere, DIPEA (0.175 ml, 1.0 mmol) was addedfollowed by the addition (slowly added) of a solution of6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyridin-3-amine(Intermediate 15, 27 mg, 0.1 mmol) in dry DCM (2 ml) and the reactionmixture was stirred for 15 minutes at the same temperature. After that asolution of Methyl 2-amino-2-methylpropanoate hydrochloride (30 mg, 0.2mmol) in dry DCM (2 ml) was added and the reaction mixture was stirredfor 30 minutes at 0° C. The reaction was quenched with a 1M aqueoussolution of HCl (5 ml), diluted with DCM (10 ml) and two phases wereseparated. The organic layer was washed with brine (10 ml), dried(Na₂SO₄), filtered and evaporated affording the urea intermediate asyellow foam.

The urea was dissolved in MeOH (5 ml), NaOMe (10 mg, 0.19 mmol) wasadded and the reaction mixture was stirred for 15 minutes at roomtemperature. The reaction was quenched with an aqueous saturatedsolution of ammonium chloride (20 ml) and diluted with ethyl acetate (40ml). Two phases were separated and the organic layer was dried (Na₂SO₄),filtered and evaporated and the residue was purified by flashchromatography (Biotage system) on silica gel using a 10 g SNAP columnand cyclohexane/ethyl acetate 75:25 to cyclohexane/ethyl acetate 25:75as eluents affording the title compound (23 mg) as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ ppm: 8.62 (1H, s), 8.14 (1H, d), 7.86 (1H,dd), 7.05 (1H, d), 6.92 (1H, d), 6.43 (1H, d), 4.44 (2H, s), 2.14 (3H,s), 1.40 (6H, s), 1.08-1.13 (2H, m), 0.96 (3H, t), 0.85-0.90 (2H, m).LC/MS: QC_3_MIN: Rt=2.016 min; 380 [M+H]+.

The following Reference Examples were prepared as described inWO2012/076877:

Reference Example RE1(5R)-5-ethyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione

Reference Example RE2(5R)-5-ethyl-5-methyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione

Reference Example RE33-(1,1-dimethylethyl)-4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)benzonitrile

Reference Example RE44-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-(1-methylethyl)benzonitrile

Reference Example RE53-cyclopropyl-4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)benzonitrile

Reference Example RE64-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-(1-methylethyl)benzonitrile

Reference Example RE74-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-[(trifluoromethyl)oxy]benzonitrile

Reference Example RE84-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-[(1-methylethyl)oxy]benzonitrile

Reference Example RE9(5R)-5-ethyl-3-[6-(spiro[1-benzofuran-3,1′-cyclopropan]-4-yloxy)-3-pyridinyl]-2,4-imidazolidinedione

Reference Example RE105,5-dimethyl-3-[6-(spiro[1-benzofuran-3,1′-cyclopropan]-4-yloxy)-3-pyridinyl]-2,4-imidazolidinedione

Biological Example 1

The ability of the compounds of the invention to modulate thevoltage-gated potassium channel subtypes Kv3.2 or Kv3.1 may bedetermined using the following assay. Analogous methods may be used toinvestigate the ability of the compounds of the invention to modulateother channel subtypes, including Kv3.3 and Kv3.4.

Cell Biology

To assess compound effects on human Kv3.2 channels (hKv3.2), a stablecell line expressing hKv3.2 was created by transfecting Chinese HamsterOvary (CHO)-K1 cells with a pCIH5-hKv3.2 vector. Cells were cultured inDMEM/F12 medium supplemented by 10% Foetal Bovine Serum, lxnon-essential amino acids (Invitrogen) and 500 ug/ml of Hygromycin-B(Invitrogen). Cells were grown and maintained at 37° C. in a humidifiedenvironment containing 5% CO₂ in air.

To assess compound effects on human Kv3.1 channels (hKv3.1),CHO/Gam/E1A-clone22 alias CGE22 cells were transduced using a hKv3.1BacMam reagent. This cell line was designed to be an improvedCHO-K1-based host for enhanced recombinant protein expression ascompared to wild type CHO-K1. The cell line was generated following thetransduction of CHO-K1 cells with a BacMam virus expressing theAdenovirus-Gam1 protein and selection with Geneticin-G418, to generate astable cell line, CHO/Gam-A3. CHO/Gam-A3 cells were transfected withpCDNA3-E1A-Hygro, followed by hygromycin-B selection and FACS sorting toobtain single-cell clones. BacMam-Luciferase and BacMam-GFP viruses werethen used in transient transduction studies to select the clone based onhighest BacMam transduction and recombinant protein expression. CGE22cells were cultured in the same medium used for the hKv3.2 CHO-K1 stablecell line with the addition of 300 ug/ml hygromycin-B and 300 ug/mlG418. All other conditions were identical to those for hKv3.2 CHO-K1cells. The day before an experiment 10 million CGE22 cells were platedin a T175 culture flask and the hKv3.1 BacMam reagent (pFBM/human Kv3.1)was added (MOI of 50). Transduced cells were used 24 hours later.

Cell Preparation for Ion Works Quattro™ Experiments

The day of the experiment, cells were removed from the incubator and theculture medium removed. Cells were washed with 5 ml of Dulbecco's PBS(DPBS) calcium and magnesium free and detached by the addition of 3 mlVersene (Invitrogen, Italy) followed by a brief incubation at 37° C. for5 minutes. The flask was tapped to dislodge cells and 10 ml of DPBScontaining calcium and magnesium was added to prepare a cell suspension.The cell suspension was then placed into a 15 ml centrifuge tube andcentrifuged for 2 min at 1200 rpm. After centrifugation, the supernatantwas removed and the cell pellet re-suspended in 4 ml of DPBS containingcalcium and magnesium using a 5 ml pipette to break up the pellet. Cellsuspension volume was then corrected to give a cell concentration forthe assay of approximately 3 million cells per ml.

All the solutions added to the cells were pre-warmed to 37° C.

Electrophysiology

Experiments were conducted at room temperature using IonWorks Quattro™planar array electrophysiology technology (Molecular Devices Corp.) withPatchPlate™ PPC. Stimulation protocols and data acquisition were carriedout using a microcomputer (Dell Pentium 4). Planar electrode holeresistances(Rp) were determined by applying a 10 mV voltage step acrosseach well. These measurements were performed before cell addition. Aftercell addition and seal formation, a seal test was performed by applyinga voltage step from −80 mV to −70 mV for 160 ms. Following this,amphotericin-B solution was added to the intracellular face of theelectrode to achieve intracellular access. Cells were held at −70 mV.Leak subtraction was conducted in all experiments by applying 50 mshyperpolarizing (10 mV) prepulses to evoke leak currents followed by a20 ms period at the holding potential before test pulses. From theholding potential of −70 mV, a first test pulse to −15 mV was appliedfor 100 ms and following a further 100 ms at −70 mV, a second pulse to40 mV was applied for 50 ms. Cells were then maintained for a further100 ms at −100 mV and then a voltage ramp from −100 mV to 40 mV wasapplied over 200 ms. Test pulses protocol may be performed in theabsence (pre-read) and presence (post-read) of the test compound. Pre-and post-reads may be separated by the compound addition followed by a 3minute incubation.

Solutions and Drugs

The intracellular solution contained the following (in mM): K-gluconate100, KCl 54, MgCl₂ 3.2, HEPES 5, adjusted to pH 7.3 with KOH.Amphotericin-B solution was prepared as 50 mg/ml stock solution in DMSOand diluted to a final working concentration of 0.1 mg/ml inintracellular solution. The external solution was Dulbecco's PhosphateBuffered Saline (DPBS) and contained the following (in mM): CaCl₂ 0.90,KCl 2.67, KH₂PO₄ 1.47, MgCl.6H₂O 0.493, NaCl 136.9, Na₃PO₄ 8.06, with apH of 7.4.

Compounds of the invention (or reference compounds such asN-cyclohexyl-N-[(7,8-dimethyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]-N′-phenylureawere dissolved in dimethylsulfoxide (DMSO) at a stock concentration of10 mM. These solutions were further diluted with DMSO using a Biomek FX(Beckman Coulter) in a 384 compound plate. Each dilution (1 μL) wastransferred to another compound plate and external solution containing0.05% pluronic acid (66 μL) was added. 3.5 μL from each plate containinga compound of the invention was added and incubated with the cellsduring the IonWorks Quattro™ experiment. The final assay dilution was200 and the final compound concentrations were in the range 50 μM to 50nM.

Data Analysis

The recordings were analysed and filtered using both seal resistance(>20 MO) and peak current amplitude (>500 pA at the voltage step of 40mV) in the absence of compound to eliminate unsuitable cells fromfurther analysis. Paired comparisons between pre- and post−drugadditions measured for the −15 mV voltage step were used to determinethe positive modulation effect of each compound. Kv3 channel-mediatedoutward currents were measured determined from the mean amplitude of thecurrent over the final 10 ms of the −15 mV voltage pulse minus the meanbaseline current at −70 mV over a 10 ms period just prior to the −15 mVstep. These Kv3 channel currents following addition of the test compoundwere then compared with the currents recorded prior to compoundaddition. Data were normalised to the maximum effect of the referencecompound (50 microM ofN-cyclohexyl-N-[(7,8-dimethyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]N′-phenylurea)and to the effect of a vehicle control (0.5% DMSO). The normalised datawere analysed using ActivityBase or Excel software. The concentration ofcompound required to increase currents by 50% of the maximum increaseproduced by the reference compound (EC50) was determined by fitting ofthe concentration-response data using a four parameter logistic functionwith ActivityBase or XL-fit software.

N-cyclohexyl-N-[(7,8-dimethyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]N′-phenylureawas obtained from ASINEX (Registry Number: 552311-06-5).

All of the Example compounds were tested in the above assay measuringpotentiation of Kv3.1 or Kv3.2 or Kv3.1 and Kv3.2 (herein after “Kv3.1and/or Kv3.2”). Kv3.1 and/or Kv3.2 positive modulators produce in theabove assay an increase of whole-cell currents of, on average, at least20% of that observed with 50 microMN-cyclohexyl-N-[(7,8-dimethyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]N′-phenylurea.Thus, in the recombinant cell assays of Biological Example 1, all of theExample compounds act as positive modulators of Kv3.1 and Kv3.2channels. As used herein, a Kv3.1 and/or Kv3.2 positive modulator is acompound which has been shown to produce at least 20% potentiation ofwhole-cell currents mediated by human Kv3.1 and/or human Kv3.2 channelsrecombinantly expressed in mammalian cells, as determined using theassays described in Biological Example 1 (Biological Assays).

A secondary analysis of the data from the assays described in BiologicalExample 1 may be used to investigate the effect of the compounds on rateof rise of the current from the start of the depolarising voltagepulses. The magnitude of the effect of a compound can be determined fromthe time constant (Tau_(act)) obtained from a non-linear fit, using theequation given below, of the rise in Kv3.1 or Kv3.2 currents followingthe start of the −15 mV depolarising voltage pulse.

Y=(Y0−Ymax)*exp(−K*X)+Ymax

where:

-   -   Y0 is the current value at the start of the depolarising voltage        pulse;    -   Ymax is the plateau current;    -   K is the rate constant, and Tau_(act) is the activation time        constant, which is the reciprocal of K.

Similarly, the effect of the compounds on the time taken for Kv3.1 andKv3.2 currents to decay on closing of the channels at the end of the −15mV depolarising voltage pulses can also be investigated. In this lattercase, the magnitude of the effect of a compound on channel closing canbe determined from the time constant (Tau_(deact)) of a non-linear fitof the decay of the current (“tail current”) immediately following theend of the depolarising voltage pulse.

The time constant for activation (Tau_(act)) has been determined for allof the compounds of the Examples. FIG. 1 shows the data for twocompounds. Table 1 provides the Tau_(act) data for all of the Examplesanalysed in this way.

FIG. 1a shows hKv3.2 currents recorded using the assay described inBiological Example 1. Data shown are the individual currents over theperiod of the depolarising voltage step to −15 mV recorded from 4different cells at two concentrations of compound (Reference ExampleRE1). The data are fitted by a single exponential curve (solid lines)using the fitting procedure in Prism version 5 (Graphpad Software Inc).

FIG. 1b shows hKv3.2 currents recorded using the assay described inBiological Example 1. Data shown are the individual currents over theperiod of the depolarising voltage step to −15 mV recorded from 2different cells at two concentrations of the compound of ReferenceExample RE3. The data are fitted by a single exponential curve (solidlines) using the fitting procedure in Prism version 5 (Graphpad SoftwareInc).

TABLE 1 Summary hKv3.2 data from the analysis of activation time(Tau_(act)). Concentration Tau_(act) Standard Number of Example (μM)mean (ms) Deviation experiments Vehicle — 7.1 1.7 6 (cells) RE1 6.25 9.92.2 5 RE2 12.5 7.3 1.8 4 RE3 0.2 23.0 6.2 4 RE4 0.8 9.2 2.3 2 RE5 3.113.0 2.3 2 RE6 3.1 8.2 2.0 2 RE7 3.1 10.4 2.8 2 RE8 3.1 9.7 1.0 2 RE90.2 50.1 7.5 5 RE10 0.4 19.3 1.0 4 Example 9 0.8 24.0 3.6 2 Example 60.4 34.8 4.9 2 Example 5 0.8 31.5 4.0 2 Example 1 1.6 21.3 0.1 2 Example2 1.6 14.8 1.9 2 Example 7 0.4 28.0 0.4 2 Example 8 1.6 25.0 2.1 2Example 4 1.6 13.1 0.7 4 Example 3 25.0 8.9 1.0 2 Example 10 1.6 17.30.7 2 To allow for comparison between compounds, the compoundconcentration chosen was that which produced a similar current (~0.3 nA)at the end of the voltage pulse, with the exception of the vehicle,where maximum currents were < 0.1 nA.

As can be seen from Table 1, in the absence of compound and presence ofvehicle the Tau_(act) was 7.1±1.7 msec. A range of Tau_(act) values(7.3-50.1 msec) was observed in the presence of the test compounds wheneach was tested at a concentration that increased the Kv3.2 current to asimilar level (^(˜)0.3 nA).

Kv3.1 and Kv3.2 channels must activate and deactivate very rapidly inorder to allow neurons to fire actions potentials at high frequency(Rudy and McBain, 2001, Trends in Neurosciences 24, 517-526). Slowing ofactivation is likely to delay the onset of action potentialrepolarisation; slowing of deactivation could lead to hyperpolarisingcurrents that reduce the excitability of the neuron and delay the timebefore the neuron can fire a further action potential. Together theseslowing effects on channel activation and deactivation are likely tolead to a reduction rather than a facilitation of the neurons ability tofire at high frequencies. Thus compounds that have this slowing effecton the Kv3.1 and/or Kv3.2 channels may slow neuronal firing. Thisslowing of neuronal firing by a compound, such as Reference Example 9which markedly increases Tau_(act) to 50.1±7.5 msec (Table 1), can beobserved from recordings made from “fast-firing” interneurons in thecortex of rat brain, using electrophysiological techniques, in vitro. Ascan be observed in FIG. 2, the addition of Reference Example 9 reducesthe ability of the neurons to fire in response to trains of depolarisingpulses at 300 Hz.

FIG. 2 shows recordings made from identified “fast-firing” interneuronsin the somatosensory cortex of the mouse. The neurons are induced tofire at high frequencies by trains of high frequency depolarisingcurrent pulses at 100, 200, and 300 Hz. The ability of the neuron tofire an action potential on each pulse is determined. A spikeprobability of 1 on the y-axis of the graph indicates that an actionpotential is generated by the neuron on each of the depolarising currentpulses. In the absence of drug (closed circles, n=9), the neuronsmaintained a spike probability of 1 up to 300 Hz. However, in thepresence of Reference Example 9 (1 microM; open circles, n=6), theneurons were unable to follow trains at the highest frequency. *p<0.05,ANOVA for repeated measures.

Therefore, although all the Examples herein identified act as positivemodulators in the recombinant cell assay of Biological Example 1, thosecompounds which markedly increase the value of Tau_(act), may reduce theability of neurons in native tissues to fire at high frequency.

Biological Example 2 Psychostimulant-Induced Hyperactivity in MiceExperimental Preparation

Male CD-1 mice (25-35 g) were supplied by Charles River, Italy. Animalswere group housed with free access to food (Standard rodent chow) andwater under a 12 h light/dark cycle (lights on at 0600 h). A period ofat least 5 days between arrival and the study was allowed in all cases.

Experimental Protocol

Animals were administered a test compound at the appropriate dose, routeand pre-treatment time, and then returned to their home cage. Testingoccurred in a separate room from that used for housing. Mice weretreated with the test compound and placed individually into a Perspexbox (length 20.5 cm, width 20.5 cm, height 34 cm) covered with aperforated lid. Infrared monitoring sensors were located around theperimeter walls (horizontal sensors). Two additional sensors werelocated 2.5 cm above the floor on opposite sides (vertical sensors).Data were collected and analysed using a VersaMax System (AccuscanInstruments Inc., Columbus, Ohio) which in turn transferred informationto a computer. After 30 minutes of habituation to the test arena, micewere treated with amphetamine (2 mg/kg) dosed intraperitoneally (i.p.)at 10 mL/kg, and subsequent locomotor activity in the test arena wasassessed over a further 60 minutes. Locomotor activity in the horizontalplane was determined from the number of interuptions of the horizontalsensors by each mouse in the test arena over the 60 minute test period.

Drugs and Materials

All doses were calculated as base. Clozapine was dissolved in distilledwater and dosed at 3 mg/kg intraperitoneum (i.p.) at 10 mL/kg. Example 4(3, 10, or 30 mg/kg) or vehicle (Captisol 20%+Tween 80 0.1% and HPMC0.5% in sterile water) was administered i.p. at 10 mL/kg. Both clozapineand Example 4 were dosed immediately before placing the animal in thetest arena (30 minutes before amphetamine administration).

Analysis of Blood Levels of Example 4

Blood samples were collected from a subset of study mice (n=3) at theend of the behavioural measurement (90 minutes post-dose of test drug),and assayed using a method based on protein precipitation withacetonitrile followed by HPLC-MS/MS analysis with an optimizedanalytical method. Since the stability of the analyte in blood and brainwas unknown, Calibration standards (CS) and Quality control samples (QC)were prepared on the day of dosing and stored together with studysamples. Study samples, CS, QC and blanks were spiked with rolipram asinternal standard (IS). Study samples were analyzed in discrete batchestogether with CS, QC and blank samples.

Results

Amphetamine alone produced a large and significant increase in totallocomotor activity. A dose of 10 mg/kg i.p. of Example 4 significantlyreduced the increase in total locomotor activity produced byamphetamine. A higher dose of 30 mg/kg i.p. of Example 4 further reducedthe increase in locomotor activity induced by amphetamine in a mannersimilar to the positive control, clozapine (3 mg/kg i.p.). Data aresummarised in Table 1.

TABLE 1 Effects of Example 4 on amphetamine induced hyperlocomotion inthe mouse. Locomotor activity Blood concentration of Treatment (beamcrosses) Test Drug (ng/mL) Vehicle  5116 ± 1040*** n.d. Amphetamine(AMPH) 16190 ± 2394 n.d. 2.0 mg/kg AMPH 2 mg/kg + 10263 ± 2443  98[34-168] Example 4 3 mg/kg AMPH 2 mg/kg +  9015 ± 1413*  244 [215-300]Example 4 10 mg/kg AMPH 2 mg/kg +  4555 ± 922*** 2140 [1790-2380]Example 4 30 mg/kg AMPH 2 mg/kg +  1546 ± 420*** n.d. Clozapine mg/kgExample 4 was administered i.p. 30 minutes before amphetamine (2 mg/kgi.p.). Clozapine was administered i.p. 30 minutes before amphetamine (2mg/kg i.p.). Locomotor activity was assessed over 60 minutes startingimmediately after amphetamine administration. Data are expressed as mean± sem. Data were subjected to one-way analysis of variance (ANOVA)followed by Dunnett's test (***p < 0.001, *p < 0.05 vs amphetaminetreatment alone). Blood concentrations were determined from a subset of3 mice at the end of the experiment, 90 minutes after test drugadministration. Data shown are the mean blood concentrations and range.(n.d. = not determined).

CONCLUSIONS

These results show that Example 4 is able to prevent hyperactivityinduced by the psychostimulant, amphetamine. Thus, Example 4 and othercompounds that positively modulate Kv3.1 and/or Kv3.2 channels, in theabsence of effects on channels gating kinetics, as can be observed fromthe assay described in Biological Example 1, may be useful in thetreatment of disorders associated with hyperactivity, such as bipolarmania, or disruption of the dopamine system, such that may occur in drugdependence, attention deficit hyperactivity disorder (ADHD), orschizophrenia.

Further illustrations of the potential utility of compounds of thepresent invention are provided, for example, in WO2012/076877 whichassociates the use of Kv3.1 and/or Kv3.2 channel modulators with anumber of disorders.

1-24. (canceled)
 25. A method for the treatment or prophylaxis ofanxiety disorders, which comprises administering to a subject in needthereof a compound of formula (I):

wherein: W is CR_(a)R_(b) or O; when W is CR_(a)R_(b) then Z is CH₂;when W is O then Z is CF₂; R_(a) and R_(b) are CH₃ or taken togetherform a C₃ spiro cycloalkyl; wherein, when W is CR_(a)R_(b), Z is CH₂ andR_(a) and R_(b) are CH₃: Ring A is:

 and Ring B is:

or Ring A is:

 and Ring B is:

wherein, when W is CR_(a)R_(b), Z is CH₂ and R_(a) and R_(b) takentogether form a C₃ spiro cycloalkyl: Ring A is:

 and Ring B is:

 and wherein, when W is O and Z is CF₂: Ring A is:

 and Ring B is:

or a pharmaceutically acceptable salt and/or solvate thereof.
 26. Themethod according to claim 25, wherein W is CR_(a)R_(b), Z is CH₂ andR_(a) and R_(b) are CH₃, and: Ring A is:

and Ring B is:

or Ring A is:

and Ring B is:


27. The method according to claim 25, wherein W is CR_(a)R_(b), Z is CH₂and R_(a) and R_(b) taken together form a C₃ spiro cycloalkyl, and: RingA is:

and Ring B is:


28. The method according to claim 25, wherein W is O and Z is CF₂: RingA is:

and Ring B is:


29. The method according to claim 25, wherein the compound of formula(I) is:(5R)-5-ethyl-5-methyl-3-[2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2,4-dione


30. The method according to claim 25, wherein the compound of formula(I) is:(5R)-5-ethyl-5-methyl-3-{2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}-2,4-imidazolidinedione


31. The method according to claim 25, wherein the compound of formula(I) is:(5R)-3-{2-[(2,2-difluoro-7-methyl-1,3-benzodioxol-4-yl)oxy]-5-pyrimidinyl}-5-ethyl-5-methyl-2,4-imidazolidinedione


32. The method according to claim 25, wherein the compound of formula(I) is:5,5-dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2,4-dione


33. The method according to claim 25, wherein the compound of formula(I) is:(5R)-5-ethyl-3-[2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2,4-dione


34. The method according to claim 25, wherein the compound of formula(I) is:(5R)-5-ethyl-3-[6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-2,4-dione


35. The method according to claim 25, wherein the compound of formula(I) is a pharmaceutically acceptable salt of(5R)-5-ethyl-3-[6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-2,4-dione


36. The method according to claim 25, wherein the compound of formula(I) is:(5R)-5-ethyl-3-{6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione


37. The method according to claim 25, wherein the compound of formula(I) is a pharmaceutically acceptable salt of(5R)-5-ethyl-3-{6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione


38. The method according to claim 25, wherein the compound of formula(I) is:(5R)-5-ethyl-3-{2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}-2,4-imidazolidinedione


39. The method according to claim 25, wherein the compound of formula(I) is:(5R)-5-ethyl-5-methyl-3-[6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-2,4-dione


40. The method according to claim 25, wherein the compound of formula(I) is a pharmaceutically acceptable salt of(5R)-5-ethyl-5-methyl-3-[6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-2,4-dione


41. The method according to claim 25, wherein the compound of formula(I) is:5,5-dimethyl-3-[6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-2,4-dione


42. The method according to claim 25, wherein the compound of formula(I) is a pharmaceutically acceptable salt of5,5-dimethyl-3-[6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-2,4-dione